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.     

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.     

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.     

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.     

Stereoselective functionalization of 2-(1-aminoalkyl)aziridines via lithiation of aziridine-borane complexes

Highly selective functionalization of the aziridine ring of (2S,1'S)-2-(1'-aminoalkyl)aziridines 1, through successive formation of aziridine-borane complexes, lithiation, treatment with a variety of electrophiles and final decomplexation is described. The influence of the structure of the starting complexes 2 and of the electrophiles in the stereoselectivity of this process has been studied. Finally, successive double lithiation-electrophile reactions were carried out affording enantiopure 1,2,3,3-tetrasubstituted aziridine-borane complexes with high selectivity.     

An efficient synthesis of cyanoarenes and cyanoheteroarenes via lithiation followed by electrophilic cyanation

A one-pot procedure for the conversion of mono-substituted arenes and heteroarenes into the ortho-cyano derivatives was achieved through directed lithiation followed by electrophilic cyanation with phenyl cyanate. This reaction method proved to be applicable to halogen-lithium exchanged intermediates, so especially useful for the synthesis of benzonitriles. The scope of the reaction sequence was explored using a number of substrates.     

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.     

Convenient synthesis of 1,2,3,4-tetrahydroquinolines via direct intramolecular reductive ring closure

A simple and convenient procedure for the synthesis of 3-aryl-1,2,3,4-tetrahydroquinolines is reported. 3-Aryl-1,2,3,4-tetrahydroquinolines are directly obtained by reductive ring closure of 2-phenyl-3-(2-nitrophenyl)-propionitrile derivatives in moderate to high yields.     

Determination of arsenic in gold by flow injection inductively coupled plasma mass spectrometry with matrix removal by reductive precipitation

Arsenic was determined in gold by flow injection hydride generation inductively coupled plasma-mass spectrometry following a batch mode reductive precipitation removal of the interfering gold matrix. A solution of potassium iodide, L-ascorbic acid, and hydrochloric acid was used as the reluctant. The recovery of gold by precipitation and filtration was 99 ± 3%. The detection limit for arsenic in gold was 55 ng g⁻¹ in the solid. The concentration of arsenic that was determined in the Royal Canadian Mint gold sample FAU-10 was 29.7 μg g⁻¹ in the solid; this value was indistinguishable, with 95% confidence, from values determined at the Royal Canadian Mint by graphite furnace atomic absorption spectrometry and by inductively coupled plasma-mass spectrometry. The standard deviation for four replicate determinations of the arsenic in FAU-10 was 0.972 μg g⁻¹ in the solid.     

An efficient route to 2,3-disubstituted indoles via reductive alkylation using H2 as reductant

An efficient route to 2,3-disubstituted indoles was developed via reductive alkylation of 2-substituted indoles using hydrogen as a clean and atom economic reductant under ambient pressure.     

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.     

Iron triflate catalyzed reductive amination of aldehydes using sodium borohydride

An efficient and convenient procedure for the reductive amination of aldehydes using NaBH₄ in the presence of catalytic amount of Fe(OTf)₃ is described.     

A sort synthesis of polyhydroxylated pyrrolizidines via sequential 1,3-dipolar cycloaddition and reductive amination

Polyhydroxylated pyrrolizidines bearing a methyl group at C-5 have been synthesized by 1,3-dipolar cycloaddition of five membered cyclic nitrones with methyl vinyl ketone followed by a N–O reductive cleavage and in situ intramolecular reductive amination. The stereochemistry of the obtained compounds is examined in relation to the reactions mechanism.     

Stereoselective synthesis of substituted N-heterocycles via sequential cross metathesis—reductive cyclization

A diastereoselective synthesis of substituted mono- and bicyclic-piperidine and pyrrolidine derivatives is presented, employing a highly selective cross metathesis (CM) reaction followed by a domino reduction-cyclization process.     

Efficient synthesis of new chiral 1,2-benzothiazin-3-one 1,1-dioxide derivatives via lateral lithiation of 3-N-mesitylenesulfonyl-1,3-oxazolidin-2-ones

Chiral 3-N-mesitylenesulfonyl-1,3-oxazolidin-2-ones 4a-e derived from (l)- and (d)-amino acids 1a-e undergo lateral lithiation with lithium diisopropylamide and TMEDA in anhydrous THF to provide new optically-active 1,2-benzothiazin-3-one 1,1-dioxide derivatives 5a-e with yields ranging from 63% to 79%.     

The reductive etherification of carbonyl compounds using polymethylhydrosiloxane activated by molecular iodine

Aldehydes and ketones undergo a smooth reductive etherification by polymethylhydrosiloxane (PMHS) in the presence of a catalytic amount of molecular iodine under mild conditions to afford the corresponding symmetrical ethers in excellent yields. This new reagent system (PMHS/I₂) provides a simple and convenient route for the preparation of symmetrical ethers from carbonyl compounds.     

Syntheses of new polyamine dendrimer units via a tandem hydroformylation/reductive amination sequences

Rh-catalyzed tandem hydroformylation/reductive amination sequences (hydroaminomethylation) starting from olefins are applied to the synthesis of new polyamine dendrimer units using both convergent and divergent strategies in solution as well as on solid support.     

Synthesis of novel serotonergics and other N-alkylamines using simple reductive amination using catalytic hydrogenation with Pd/C

Formation of N-alkylated α-methyltryptamine derivatives (2) was accomplished by simple reductive amination of amine (1) with ketones using catalytic hydrogenation conditions (3 atm H₂ and 10% Pd on carbon). This method was also applied to other primary and secondary amines using ketones and aldehydes.     

Generation of quaternary centers by reductive cross-coupling: shifting of regioselectivity in a subset of allylic alcohol-based coupling reactions

Regioselective titanium alkoxide-mediated reductive cross-coupling reactions of allylic alcohols with vinylsilanes and imines have previously been demonstrated to proceed with allylic transposition by formal metallo-[3,3]-rearrangement [thought to proceed by a sequence of: (1) directed carbometalation, and (2) syn-elimination]. While many examples have been described that support this reaction path, a collection of substrates have recently been identified that react by way of an alternative pathway, delivering a concise convergent route to coupled products bearing a quaternary center.