β-Trifluoromethyl-α-functionalized-vinyl sulfides as a potential synthetic intermediate

The β-(trifluoromethyl)vinyl sulfides on treatment with n-BuLi/TMEDA at −78 °C were readily lithiated at an α-position of the sulfanyl group, and the generated β-trifluoromethyl-α-sulfanylvinyl anions were reacted with a variety of electrophiles to give the corresponding β-trifluoromethyl-α-functionalized-vinyl sulfides 4aa-4aq in good to excellent yields. The reactivity of some products has been examined. The palladium-catalyzed cross-coupling reaction as well as homo-coupling reaction of 4af provided the corresponding products in good yields, respectively. The Diels-Alder reaction of cyclic dienes and 14 derived from 4ao provided the desired six-membered cyclic products with high endo-trifluoromethyl group selectivity.     

Enantioselective synthesis of planar chiral azaferrocenes via chiral ligand-mediated ring- and lateral-lithiations

Lithiation of 1′,2′,3′,4′,5′-pentamethylazaferrocene (1) with sec-BuLi/(−)-sparteine (3) in Et₂O at −78°C followed by quenching with electrophiles gave the ring-substituted products 2 in 74-81% ee. On the other hand, lithiation of 1′,2,2′,3′,4′,5,5′-heptamethylazaferrocene (6) with sec-BuLi in the presence of S-valine-derived bis(oxazoline) 5 in Et₂O at −55°C and subsequent reaction with electrophiles afforded the laterally functionalized products 7 in excellent enantioselectivity (96-99% ee).     

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.     

Synthesis and electrochemical studies of ferrocene-dithiafulvalenes (Fc-DTF) and 1,1′-bis(dithiafulvalenyl)ferrocene (DTF-Fc-DTF). An approach towards new conducting organic materials

Novel π-conjugated donor compounds based on the strong electron-donating ferrocene moiety and dithiafulvalene donors exhibited increased electron donor ability. The ferrocenylketones 4a,b, 5, 8 and 9 were synthesized via described methods, and allowed to react with 2-dimethoxyphosphinyl-1,3-benzodithiole (13) in the presence of n-BuLi at −78°C in dry THF to afford the corresponding ferrocene-dithiafulvalenes 14a,b, 18, 19 and 1,1′-bis(benzo-1,3-dithiol-2-ylidene)ethyl]ferrocene (15). Electrochemical properties of these new donor compounds were studied using cyclic voltammetry (CV) and UV-Vis spectra. CV and absorption spectra of the new compounds were studied in comparison with ferrocene (6) and dibenzo-tetrathiafulvalene DB-TTF 3. Two-electron and three-electron redox behaviors were observed as two waves. The absorption spectra showed a red-shift with a slight increase in the absorption intensities.     

Functionalisation of the upper rim of calix[4]arene via alcoholysis and hydrosilylation reactions

Metalation of 5,17-dibromo-25,26,27,28-tetra propoxy calix[4]arene (1) with n-BuLi in THF at −78 °C gave organolithium reagent, which reacted with Me₂HSiCl to give 5,17-bis(dimethylsilyl)-25,26,27,28-tetra propoxy calix[4]arene (2). The Si-H groups of calixarene 2 were treated with methanol, ethanol, propanol, butanol, pentanol, hexanol, 2-propanol and 2-methyl propanol in the presence of Karstedt catalyst (platinum(0)-1,3-divinyl-1,1,3,3-tetramethyl disiloxane complex, solution in xylene) to give the corresponding 5,17-bis(alkoxydimethylsilyl)-25,26,27,28-tetra propoxy calix[4]arene (3). Moreover, calixarene 2 was easily functionalized with a variety of alkenes using Karstedt catalyst to give the corresponding organosilylated calix[4]arene (4).     

Straightforward synthesis of 1,6-dioxaspiro[4.4]nonanes

Diols 2, easily prepared by a DTBB-catalysed lithiation of the dithioether 1 in the presence of different carbonyl compounds, react with ozone in dichloromethane at −78 °C leading, after treatment with thiourea at 20 °C, to the corresponding substituted 1,6-dioxaspiro[4.4]nonanes 3.     

Dibenzothiepins, phthalans and phthalides from 4-heterosubstituted dibenzothiins

The lithiation of 4-heterosubstituted dibenzothiins 1 (phenoxathiin, phenothiazine and thianthrene) with lithium and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 7.5% molar) in THF at temperatures ranging from −90 to −78°C gives the corresponding functionalised organolithium intermediate I, which by reaction with different electrophiles [H₂O, D₂O, Bu^tCHO, PhCHO, Ph(CH₂)₂CHO, Me₂CO, Et₂CO, (CH₂)₅CO, (CH₂)₇CO] at the same temperature, followed by hydrolysis, gives the expected functionalised thiols 2. Cyclisation of some thiols 2 under acidic conditions leads to the corresponding seven-membered dibenzo heterocycles 5. In the case of thianthrene 1c, after addition of a carbonyl compound as the first electrophile [MeCHO, Bu^tCHO, Me₂CO, Et₂CO, (CH₂)₅CO], the corresponding intermediate II can be lithiated again and react with a second electrophile. Diols 3 are obtained after hydrolysis when a carbonyl compound [Bu^tCHO, PhCHO, Ph(CH₂)₂CHO, Me₂CO, Et₂CO, (CH₂)₅CO] is used as the second electrophile. Acidic cyclisation of diols 3 gives substituted phthalans 6 in almost quantitative yields. Finally, in the case of using carbon dioxide as the second electrophile, phthalides 4 are obtained after acidic hydrolysis.     

Preparation of differentially 1,3-disubstituted indolines by intramolecular carbolithiation

The ether-soluble dilithio species (2), derived from N-allyl-2-bromoaniline (1) upon treatment with t-BuLi at −78°C, cyclizes when warmed to +5°C in the presence of TMEDA to give a (1-lithio-3-indolinyl)methyllithium (3) that may be differentially functionalized by sequential addition of electrophiles. The cyclization of 2 to 3 proceeds enantioselectively when conducted in the presence of (1S,2S)-(+)-N,O-dimethylpseudoephedrine.     

Rearrangement and fluorination of quinidinone in superacid

In HF/SbF₅ at −78 °C, quinidinone 1 yields fluoroketone 3 (50% yield). The reaction implies a cyclic carboxonium ion as an intermediate, which reacts through a concerted rearrangement and fluorination to yield ketone 3.     

Biomimetic syntheses of ineleganolide and sinulochmodin C from 5-episinuleptolide via sequences of transannular Michael reactions

Treatment of a solution of the macrocyclic norcembranoid 7 with lithium hexamethyldisilazide in THF at −78 °C to 0 °C, leads to the polycyclic norcembranoids ineleganolide 1 and sinulochmodin C (2) (65%), which are found in the corals Sinularia inelegans and Sinularia lochmodes, respectively. The conversions are believed to be biomimetic, and occur by successive transannular Michael reactions in 7. Under different temperature conditions the novel polycycle 30 is the main product, alongside small quantities of 1 and 2. The polycycle 30 is possibly produced from ineleganolide 1, following a reverse oxy-Michael reaction and two successive aldol reactions. The significance of the synthesis of ineleganolide 1, sinulochmodin C (2) and the structure 30 from 5-episinuleptolide 7, to the likely biosynthesis of the related norcembranoids scabrolide A (3), scabrolide B (4) and horiolide 31 found in Sinularia sp. is discussed.     

Lithiation of 2-(chloroaryl)-2-methyl-1,3-dioxolanes and application in synthesis of new ortho-functionalized acetophenone derivatives

2-(4-Chlorophenyl)-2-methyl-1,3-dioxolane 2a was lithiated ortho to the ketal group by treatment with butyllithium in THF at 0°C. Related 2-aryl-2-methyl-1,3-dioxolanes possessing a chlorine substituent at the meta position of the aryl group 2b,c were lithiated with butyllithium in THF at −78°C at the position between the two directing groups. The lithio species thus generated were treated with various electrophiles to give ortho-functionalized acetophenone derivatives.     

DTBB-catalysed lithiation of 1,2-bis(phenylsulfanyl)ethene: does 1-lithio-2-phenylsulfanylethene really exist?

The reaction of (Z)- or (E)-1,2-bis(phenylsulfanyl)ethene (1) with an excess of lithium and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 2.5 mol%) in the presence of a carbonyl compound as electrophile (Barbier conditions) in THF at −78 °C leads, after hydrolysis with water at temperatures ranging between −78 °C and rt, to a mixture of the corresponding (Z/E)-unsaturated 1,4-diols 2, the diastereomers ratio being independent of the stereochemistry of the starting materials. Allylic alcohols 3 are the main by-products, resulting from a lithium-hydrogen exchange on some of the lithiated intermediates along the whole process. A mechanistic explanation for the observed behaviour is given.     

Synthesis and conformational analysis of 3-hydroxypipecolic acid analogs via CSI-mediated stereoselective amination

A short and efficient stereoselective synthetic approach toward substituted piperidines, involving (2S,3S)-3-hydroxypipecolic acid 1, (2R,3S)-3-hydroxypipecolic acid 3, and their acid-reduced analogs 2 and 4, has been developed. The requisite anti- and syn-1,2-amino alcohols 11 and 12 for the preparation of title four piperidine analogs 1-4 were synthesized via the regioselective and diastereoselective amination of anti- and syn-1,2-dibenzyl ethers 13 and 14 using chlorosulfonyl isocyanate (CSI). As a result, reaction of anti-1,2-dibenzyl ether 13 with CSI afforded exclusively the anti-1,2-amino alcohol 11 with the diastereoselectivity of 49:1 in toluene at −78 °C and syn-isomer 14 gave the syn-1,2-amino alcohol 12 as the major product with the diastereoselectivity of 12:1 in hexane at −78 °C. The result of these reactions could be explained by the neighboring group effect leading to retention of stereochemistry. In addition, conformational changes of trans-piperidine intermediate 9 in terms of the nature of N-protecting groups are described. The conformations of 9 and 24-28 were confirmed by ¹H NMR analysis and NOE correlation. Furthermore, the conformations of piperidines 18 and 23 with hydroxyl methyl substituent at C-2 were investigated by NMR spectroscopy.     

1,3-Dilithio-2-(diphenylmethylene)propane

The reaction of 2,2-diphenylmethylenecyclopropane (5) with an excess of lithium and a catalytic amount of DTBB (4 mol %) in THF at −78 °C leads to the formation of dilithiated species 6-8 by reductive opening of the cyclopropane ring. Further reaction of these intermediates with different electrophiles [E = H₂O, D₂O, CH₂CMeCH₂Cl, Me₃SiCl, Me₃SiCH₂Cl, t-BuCHO, Me₂CO, Et₂CO, n-Pr₂CO, i-Pr₂CO, t-Bu₂CO, (CH₂)₅CO, Ph₂CO and adamantanone] is highly regioselective, yielding exclusively the corresponding products 9, after hydrolysis with water. However, when 3-chloro-2-(chloromethyl)propene (14) is used as a dielectrophile, the cyclisation to give a six-membered ring takes place through intermediate 6, giving compound 16 as the only reaction product.     

Mg-promoted facile and selective intramolecular cyclization of aromatic δ-ketoesters

Treatment of various types of aromatic δ-ketoesters 2, 7, and 9 with Mg-turnings for Grignard reaction at −5 to 0 °C in N,N-dimethylformamide (DMF) containing trimethylsilyl chloride (TMSCl) brought about selective and reductive intramolecular cyclization to give the corresponding α-aryl-α-hydroxycyclopentanones 5, 8, and 10, respectively, in moderate to good yields. Similar reductive intramolecular cyclization of aromatic δ-ketodiesters 14, followed by acidic hydrolysis and decarboxylation easily gave the corresponding 2-aryl-2-cyclopenten-1-ones 15. The present facile coupling may be initiated through electron transfer from Mg metal to the aromatic carbonyl groups of 2, 7, 9, and 14 to generate the corresponding radical anions, followed by their intramolecular nucleophilic attack to the ester groups to give the corresponding five-membered ring compounds 5, 8, 10, and 15, respectively.     

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.     

Ozonolysis of bis-endo-diacylbicyclo[2.2.1]heptenes in dichloromethane-methanol

Ozonolysis of bis-endo-diacylbicyclo[2.2.1]heptenes 3a-d at −78 °C in dichloromethane-methanol gave the hydroperoxides 6a-d in 70-80% yields. Ozonolysis of bis-endo-diacetylbicyclo[2.2.2]octene 15 and bis-endo-diacetyl-7-oxabicyclo-[2.2.1]heptene 16 under the same reaction conditions gave the hydroperoxides 17 and 18, respectively. The intramolecular sequential nucleophilic addition of the carbonyl groups to the carbonyl oxide group was observed for the first time and was found to be faster than the intermolecular nucleophilic addition of a methanol molecule to the carbonyl oxide group. Ozonolysis of compound 23 in CH₂Cl₂-MeOH at −78 °C followed by reduction with Me₂S gave compounds 24 and 25, in which the stereochemistry of the methoxyl groups was determined by X-ray analysis.     

Cyclopropylmethyl- and cyclobutylmethyllithium by an arene-catalyzed lithiation. Stability and reactivity

The reaction of (chloromethyl)cyclopropane 5 and (bromomethyl)cyclobutane 8 with lithium and a substoichiometric amount of DTBB, in the presence of different carbonyl compounds as electrophiles, in THF at −78 °C leads, after hydrolysis, to the corresponding cycloalkyl alcohols 6 and 9, respectively. However, when the same starting materials are lithiated using naphthalene as catalyst in diethyl ether and at higher temperature (0 or 25 °C), and then react with the same electrophiles, the final hydrolysis yields the corresponding unsaturated alcohols 7 and 10, respectively.     

Direct preparation and structure determination of tertiary and secondary amine boranes from primary or secondary amine boranes

New secondary and tertiary amine borane derivatives were prepared in a one-pot reaction starting from primary amine boranes. The reaction involves treatment of an amine borane with 2 equivalents of s-BuLi at −78 °C. In general, mixtures of mono and di metallated products were obtained. Alkyl iodides and benzyl chloride reacted with the lithiated amine, but aldehydes and ketones were reduced. Conversion was high as determined by NMR, but moderate to low yields were obtained after chromatography, possibly due to decomposition on silica. Crystal structures were obtained for the compounds 3a, 3b and 3c.     

Selective lithiation of 1,6-dihalohex-1-enes and 1,6-dihalohex-1-ynes

The lithiation of 1-choro- and 1-bromo-6-chlorohex-1-yne (2, 3) with lithium naphthalene in the presence of benzaldehyde in THF at −78 °C leads after hydrolysis with water to the corresponding chloroalkynol (5) resulting from a regioselective lithiation at the alkynylic position. However, the lithiation of 1-chloro-6-iodohex-1-yne (4) under the same reaction conditions and using pentan-3-one as electrophile leads to the corresponding chloroalcohol (6) from the exclusive lithiation at the aliphatic carbon-iodine bond. Double lithiation of compounds 2 and 3 under Barbier conditions allows the isolation of diols (9), whereas the two-step process leads to differently substituted diols 13. The monolithiation of (E)-1-bromo-6-chlorohex-1-ene (14) under the above conditions and using pentan-3-one as electrophile affords a mixture of chloroalcohols 15 and 16, the process being not stereospecific. However, the lithiation of the same starting material with t-BuLi leads exclusively to a bromine-lithium exchange with retention of the configuration, so after treatment with pentan-3-one only compound 16 was isolated. Finally, whereas double lithiation of compound 14 under the conditions for compounds 9 gives the mixture of compounds 18 and 19, the tandem process involving the t-BuLi-promoted bromine-lithium exchange as the first step followed by lithiation under DTBB-catalysed conditions allows the isolation of (E)-diols 19 as the only reaction products isolated.