Reductive opening of 2,7-dihydrodinaphthoxepine and thiepine: easy regioselective preparation of 2,2′-difunctionalised binaphthyls

The lithiation of 2,7-dihydrodinaphthoheteroepines (5) with 2.2 equiv of lithium naphthalenide in THF at −78 °C gives dianionic intermediates 8, which by reaction with different electrophiles [H₂O, D₂O, ^tBuCHO, Me₂CO, Et₂CO, (CH₂)₄CO, (CH₂)₅CO] at the same temperature, followed by hydrolysis, leads to unsymmetrically 2,2′-disubstituted binaphthyls 6. When the lithiation is performed with an excess of lithium in the presence of a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 10 mol %), a double reductive cleavage takes place to give dianionic intermediate 9, which by reaction with different electrophiles [H₂O, Me₂CO, Et₂CO, (CH₂)₄CO, (CH₂)₅CO], followed by hydrolysis with water, yields symmetrically 2,2′-disubstituted binaphthyls 7. In the case of starting from (R)-5a, the reductive opening by treatment with 2.2 equiv of lithium naphthalenide followed by reaction with H₂O or (CH₂)₅CO as electrophiles and final hydrolysis, leads to enantiomerically pure compounds (R)-6aa and (R)-6af, respectively.     

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.     

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.     

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 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.     

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.     

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.     

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.     

Titanium tetrachloride mediated reductive ring opening of C-aryl pseudoglycals

A facile reductive ring opening of C-aryl pseudoglycals is reported for the first time. The combination of titanium tetrachloride (Lewis acid) and triethylsilane (reducing agent) at −78 °C in dichloromethane is a mild and efficient reagent system for this transformation. The reagent system was successfully tested on various C-aryl pseudoglycal substrates to yield the corresponding ring opened products containing two asymmetric hydroxyls and a cis-double bond.     

Experiments towards the preparation of some binaphthalene derivatives

Oxidative dimerizations of some naphthalene derivatives were studied. With vanadium oxytrichloride either a new C-C bond formation occured or the reagent caused chlorination of the ring. Attempts to induce photochemically a new C-C bond failed.

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Versuche zur Herstellung einiger Binaphthalin-Derivate

Zusammenfassung Die oxidative Dimerisierung einiger Naphthalinderivate wurde untersucht. Mit Vanadiumoxytrichlorid wird eine neue C-C-Bindung gebildet, es wurde jedoch auch Chlorierung des Naphthalinringes beobachtet. Versuche zur photochemischen Bildung einer C-C-Bindung scheiterten.

     

Regio- and chemoselective reductive cleavage of 4,6-O-benzylidene-type acetals of hexopyranosides using BH3·THF-TMSOTf

Benzylidene-type cyclic acetals of carbohydrates undergo efficient reductive ring opening using BH₃·THF and a catalytic amount of TMSOTf at room temperature. 4,6-O-Benzylidene-hexopyranosides afford the corresponding 4-O-benzyl ethers exclusively, in high yields. Other benzylidene-type acetals, such as naphthylmethylene and 4-methoxybenzylidene acetals are also cleaved with the same reagent. The conversions are highly regio- and stereoselective and afford benzyl-type ethers in excellent yields.     

A general protocol for the regio high yielding opening of different glycidol derivatives

Differently protected glycidol derivatives (with Bn, TBDPS, TBS and MPM groups) have been tested for regioselective ring opening with vinylmagnesium bromide in order to obtain useful five-carbon functionalised homoallylic alcohols. Careful choice of the reagents and experimental conditions allowed a general access to important chiral synthons for asymmetric synthesis.     

Organolithiums by reductive lithiation: the catalytic aromatic method versus the use of preformed aromatic radical-anions. Naphthalene can behave as a catalyst or an inhibitor

Two common modes, using aromatic radical-anions for reductive lithiation, the replacement of a C-heteroatom bond with a C-Li bond, have been compared with regard to yield and the mildness of reaction conditions required. It was found that the use of preformed radical-anions generally resulted in higher yields and milder reaction conditions than the ‘catalytic’ method in which catalytic amounts of the aromatic compound are used and the radical-anion is generated and used in situ. The one apparent exception is N-phenylaziridine, but it is shown that in this case the aromatic compound, naphthalene, is actually an inhibitor rather than a catalyst. Rational mechanistic explanations are given.     

Syntheses and Structures of Binaphthyl-bridged Schiff Bases

The reaction of dinaphthofuran with lithium in anhydrous diethyl ether led to a solution of the corresponding C,O-dilithiated intermediate which, upon treatment with DMF at ？78 oC, afforded, after hydrolysis, 2＇-hydroxy-1,1＇-binaphthyl-2-carbaldehyde in a good yield. Then binaphthyl-bridged Schiff bases were prepared by the condensation of 2＇-hydroxy-1,1＇-binaphthyl-2-carbaldehyde with the corresponding aromatic amines.     

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.     

Purposeful regioselectivity control of the Birch reductive alkylation of biphenyl-4-carbonitrile

Birch's reductive alkylation of biphenyl-4-carbonitrile (1) provides alkylated 1,4-dihydroderivatives of various structural types: 4-alkyl-4-phenylcyclohexa-2,5-dienone, 1,4-dialkyl-4-phenylcyclohexa-2,5-dienecarbonitrile (with the same or different alkyl fragments), and 4-(1-alkylcyclohexa-2,5-dienyl)benzonitrile. Each of these products become dominant depending on the nature of long-living anionic form generated from 1, namely, the stable product of two-electrons reduction – dianion (1^2?); 1-alkyl-4-cyano-1-phenylcyclohexa-2,5-dien-4-yl anion (1-Alk₁^–), originated due to the alkylation of dianion 1^2? at the position 1 of biphenyl moiety; or 1-(4-cyanophenyl)cyclohexa-2,5-dien-1-yl anion (1-H_4’^–), being the product of dianion 1^2? protonation at position 4′ by protonating reagent (MeOH or NH₄Cl). The orientation of alkyl fragment incorporation into biphenyl-4-carbonitrile scaffold is in agreement with calculated electronic structure of the anionic species under investigation. The dominating type of their reactivity towards alkyl halides proved to be nucleophilic (S_N2 mechanism).     

Ring‐opening metathesis polymerization of amino acid‐functionalized norbornene derivatives

Amino acid‐derived novel norbornene derivatives, N,N′‐(endo‐bicyclo[2.2.1] hept‐5‐en‐2,3‐diyldicarbonyl) bis‐L ‐alanine methyl ester (NBA), N,N′‐(endo‐bicyclo[2.2.1]hept‐5‐en‐2,3‐diyldicarbonyl) bis‐L ‐leucine methyl ester (NBL), N,N′‐(endo‐bicyclo[2.2.1]hept‐5‐en‐2,3‐diyldicarbonyl) bis‐L ‐phenylalanine methyl ester (NBF) were synthesized and polymerized using the Grubbs 2nd generation ruthenium (Ru) catalyst. Although NBA, NBL, and NBF did not undergo homopolymerization, they underwent copolymerization with norbornene (NB) to give the copolymers with M_n ranging from 5200 to 38,100. The maximum incorporation ratio of the amino acid‐based unit was 9%, and the cis contents of the main chain were 54–66%. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 5337–5343, 2006     

One-pot derivatization of medicinally important 9-aminoacridines by reductive amination and SNAr reaction

A new highly efficient one-pot derivatization of medicinally important 9-aminoacridines (9-AA) at the amine position is described. Simple reductive amination and S_NAr reaction using easily accessible starting materials give a fast entry to novel 9-AA derivatives for biological screening.     

Promoting effects of urethane derivatives of phenols on the ring‐opening polymerization of 1,3‐benzoxazines

For the purpose of reducing the induction period of the ring‐opening polymerization of N‐methyl‐1,3‐benzoxazines, several urethanes were examined as promoters. The examined promoters 3a – d were the adducts of resorcinol and phenyl isocyanate, that of bisphenol A and phenyl isocyanate, that of resorcinol and butyl isocyanate, and that of 1,3‐propanediol and phenyl isocyanate, respectively. The aromatic urethanes 3a and 3b , which were adducts of the phenolic compounds and phenyl isocyanate, exhibited significant promoting effects. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis of enantiomerically pure tertiary 1,2-aminoalcohols by the highly diastereoselective reductive ring opening of oxazolidines

A number of enantiomerically pure 1,2-aminoalcohols containing tertiary nitrogen atoms bearing chiral substituents have been prepared by highly diastereoselective reductive ring cleavage of oxazolidines derived from ketones and pseudoephedrine or ephedrine. The ring cleavage occurs with retention of configuration.