Emma Alonso

Application of Chiral Sulfides to Catalytic Asymmetric Aziridination and Cyclopropanation with In Situ Generation of the Diazo Compound

Imines and alkenes can be converted into the corresponding aziridines and cyclopropanes (see scheme, PTC=phase-transfer catalyst, Ts=toluene-4-sulfonyl) in good yield with moderate to high d.r. and high ee values using tosylhydrazone salts with catalytic quantities of chiral sulfide (5-20 mol %) and metal catalyst (1 mol %). The process is particularly suited to the synthesis of conformationally locked cyclopropyl amino acids, which can now be prepared in only three steps from commercially available material in 100 % ee.

Catalytic asymmetric synthesis of epoxides from aldehydes using sulfur ylides with in situ generation of diazocompounds

A practical, general, and convergent route to epoxides with control of the relative and absolute stereochemistry has been achieved by generating the reactive intermediate (the diazo compound) in situ from tosylhydrazone salts (see scheme, PTC=phase-transfer catalyst, Ts=toluene-4-sulfonyl). High yields (58-82 %), high d.r. (88:12-98:2), and high ee values (87-94 %) have been obtained using a new class of stable chiral sulfides at low catalyst loading (5 mol %) and [Rh2 (OAc)4 ] (0.5 mol %).

Reductive deprotection of allyl, benzyl and sulfonyl substituted alcohols, amines and amides using a naphthalene-catalysed lithiation

Abstract The reaction of different protected alcohols, amines and amides with lithium and a catalytic amount of naphthalene (4 mol %) in THF at low temperature leads to their deprotection under very mild reaction conditions, the process being in many cases chemoselective.

Naphthalene-catalysed Lithiation of Chlorinated Nitrogenated Aromatic Heterocycles and Reaction with Electrophiles☆

Naphthalene catalysed reductive lithiation of various chloroazines (1, 7, 10, 13) in the presence of different electrophiles yields, after hydrolysis, the expected functionalised heterocycles with one (2, 8), two (11, 14a–d) and three nitrogen atoms in the ring (14e,f). This methodology allowed us to trap in situ the lithium imine derived from the reaction of 2-pyridyllithium with benzonitrile, by reaction with a Grignard reagent in the presence of titanium alkoxides. 2,4-Dimethoxypyrimidines (14a,c,d) are demethylated under acidic conditions to give the corresponding uracil derivatives 16.

α-Nitrogenated organolithium compounds from α-amidomethyl and α-aminomethyl sulfones

Abstract Successive reaction of α-amidomethyl sulfones 7a,b, derived from primary amides, with n-butyllithium and primary alkyl bromides (CH2CHCH2Br, CH2CMeCH2Br, CH2CBrCH2Br, CHCCH2Br, PhCH2Br, ButO2CCH2Br) at −90°C yields, after hydrolysis, enamides 11. The same procedure applied to α-amidomethyl sulfones 7c,d derived from secondary amides and using different electrophiles [AcOD, D2O, EtI, CH2CHCH2Br, BunI, PhCH2Br, ButO2CCH2Br, ButCHO, PhCHO, (CH2)4CO, EtOCOCl, CH3COCl, PhCOCl] gives substituted α-amidomethyl sulfones 13. Representative compounds 13 are desulfonated (Na·Hg, Na2S2O4 or Mg-MeOH) affording the amides 15. Lithiated sulfones 13 are methylenated to the corresponding acyl enamines 16 or 17 with in situ generated chloromethylmagnesium chloride. Naphthalene-catalysed lithiation of α-aminomethyl sulfone 19 in the presence of electrophiles [ButCHO, PhCHO, Et2CO, Pr2iCO, (CH2)5CO, PhCOMe] at −78 to 0°C leads, after hydrolysis with water, to the expected aminoalcohols 20. The application of this method to α-amidomethyl sulfones 7c,d using electrophiles [ButCHO, PhCHO, Et2CO, (CH2)4CO, (CH2)5CO, PhCOMe, Me3SiCl] yields fuctionalised amides 22. Representative examples of compounds 22 were hydrolysed (HCl-EtOAc or CF3CO2H), reduced (LiAlH4) or cyclised (NaH) to give aminoalcohols 24, 25 or oxazolidinones 26, respectively.

Arene-catalysed reductive desulfonylation and desulfinylation reactions: New routes for alkyllithiums

Abstract The reaction of alkyl phenyl sulfones ( 1 ) with an excess of lithium powder and a catalytic amount of naphthalene (8 mol %) in the presence of a carbonyl compound or chlorotrimethylsilane (Barbier-type conditions) in THF at temperatures ranging between −78 and 20°C leads, after hydrolysis, to the expected products ( 2 ) arising from the corresponding alkyllithium generated in situ . When the same methodology is applied to sulfolene ( 3 ) or different alkyl phenyl sulfoxides ( 6 ), cyclic sulfinates 5 or products 2 are, respectively, obtained, the yields being, in general modest.

Imidoyllithiums: Masked acyllithium reagents

Abstract The reaction of chloroimines 1 with an excess of lithium powder and a catalytic amount of naphthalene (4 mol %) in THF at −78°C leads to the corresponding imidoyllithium intermediates 2 , which by treatment with different electrophiles [Pr i CHO, Bu t CHO, n -C 5 H 11 CHO, PhCHO, Et 2 CO, (CH 2 ) 5 CO, EtOCOCl, MeOCSCl, n -C 7 H 15 CON(Me)OMe] at −78 to 20°C and final hydrolysis with water affords functionalysed imines 3 . For starting material 1a is necessary to filter off the excess of lithium at the end of the lithiation step in order to get compounds 3 , without filtration amines 4 are the reaction products isolated. Hydrolysis of compounds 3 either during chromatographic purification or by acidic hydrolysis (2 N HCl, THF) gives the expected functionalised ketones 5 .

Direct transformation of allylic and benzylic alcohols or their silylated derivatives into organolithium compounds

Abstract The reaction of allylic or benzylic alcohols 1 with n-butyllithium followed by treatment with lithium powder and a catalytic amount of DTBB (5 mol %) in THF at room temperature gives a solution of the corresponding alkyllithium reagent, which reacts in situ with different electrophiles to yield the expected products 2. Alternatively, the O-silylated derivatives of the same alcohols are lithiated under Barbier-type reaction conditions to afford the same reaction products with better yields.

Generation of allylic and benzylic organolithium reagents from the corresponding ester, amide, carbonate, carbamate and urea derivatives

Abstract The reaction of different allylic and benzylic non-enolisable esters or amides (1), carbonates (4), carbamates (6, 7) and ureas (8) with an excess of lithium powder and a catalytic amount of naphthalene (10%) in the presence of an electrophile [iPrCHO, tBuCHO, PhCHO, Me2CO, Et2CO, (CH2)5CO, Ph2CO, Me3SiCl] in THF at different temperatures (−78, −30 or 0°C) leads, after hydrolysis with water, to the corresponding allylated or benzylated products (2).

Imidoyl chlorides as starting materials for the preparation of masked acyllithium intermediates: synthetic applications

Abstract The lithiation of several imidoyl chlorides 5, catalysed by substoichiometric amounts of naphthalene, followed by reaction with different electrophiles gives, after hydrolysis, the corresponding imine derivatives 6 and 9 or amines 7, depending on the reaction conditions. The imine derivatives are easily converted into the corresponding ketones by treatment either with dilute hydrochloric acid, for N-aryl derivatives, or with silica gel, for N-alkyl derivatives. The hydroxyimines obtained react with LiAlH4 to give the corresponding 1,2-aminoalcohols, as a single diastereoisomer. The same result is found when the imine moiety is in situ reduced with lithium. The 1,2-aminoalcohols obtained are easily transformed into the corresponding 1,3-oxazolidines 11 by reaction with para-formaldehyde under acidic catalysis.