Convenient synthesis of mono- and di-β-hydroxy-β-bis(trifluoromethyl)-(di)imines from β-hydroxy-β-bis(trifluoromethyl)-ketones and (di)amines

A series of novel β-hydroxy-β-bis(trifluoromethyl)-imines (2a-j) and di(β-hydroxy-β-bis(trifluoromethyl))-diimines (3a-f) were prepared in moderate to good yields via a simple two-step approach: first, β-hydroxy-β-bis(trifluoromethyl)-ketones (1a-c) were obtained by a catalyst-free aldol reaction between liquid hexafluoroacetone sesquihydrate and ketones (acetone, acetophenone, and pinacolone, respectively); then, condensation of the latter fluorinated β-ketols 1a-c with primary amines or diamines was achieved in the presence of Lewis (montmorillonite, InBr₃, La(OTf)₃) or Brönsted (PTSA) acid catalysts. The molecular structures of mono- and di-β-hydroxy-β-bis(trifluoromethyl)-(di)imines 2e,h and 3a,f were determined and found to exhibit strong intramolecular (R)N?H-O hydrogen bonding.     

An efficient synthesis of (E)-α,β-unsaturated ketones and esters with total stereoselectivity by using chromium dichloride

(E)-α,β-Unsaturated ketones 1 or esters 2 can be obtained with complete stereoselectivity by reaction of different 2-chloro-3-hydroxy ketones 3 or esters 4 and CrCl₂. A comparative study of the results of synthesis of ketones 1 with CrCl₂ or samarium is performed. A mechanism to explain both β-elimination reactions has been proposed.     

Four- and five-coordinate magnesium compounds containing ketiminate ligands. Synthesis and characterization of L2Mg, L2Mg(LH), and L2Mg(Py), where L = MeC(O)CHC(NAr)Me

Magnesium complexes containing ketiminate ligands were synthesized and characterized. MgBu₂ reacted readily in toluene with two equiv. of [MeC(O)CHC(NHAr)Me], where Ar = 2,6-diisopropylphenyl, to generate [MeC(O)CHC(NAr)Me]₂Mg (1) in 43% yield. The four-coordinate magnesium compound 1 is very moisture sensitive and acts as a Lewis acid, accepting one equiv. of Lewis base to form five-coordinate magnesium compounds. Compound [MeC(O)CHC(NAr)Me]₂Mg[MeC(O)CHC(NHAr)Me] (2) was obtained in 57% yield from the reaction in toluene of MgBu₂ with three equiv. of [MeC(O)CHC(NHAr)Me]. Treatment of 1 with one equiv. of free ketimine ligands [MeC(O)CHC(NHAr)Me] also led to the formation of 2. The bulky η¹-ketimine of 2 can be replaced with a less bulky Lewis base such as pyridine. Treatment of 1 with excess pyridine in toluene at ambient temperature led to the formation of compound [MeC(O)CHC(NAr)Me]₂Mg[NC₅H₅] (3) as colorless crystalline solids in 51% yield. Compounds 1, 2, and 3 were characterized by NMR and X-ray crystallography. Compounds 2 and 3 showed no activity toward the polymerization of ε-caprolactone at 25 °C after 3 h. However, when the temperature was increased to 70 °C, compounds 2 and 3 efficiently catalyzed polymerization of ε-caprolactone to generate high molecular weight poly-ε-caprolactones. The polydispersity index (PDI) of these poly-ε-caprolactones is in the range 1.57-3.18.     

The synthesis of 2,4-dienyl fluoroalkyl ketones by a tandem three-stage sequence of propargyl 2-fluoroalkylvinyl ether formation, Claisen rearrangement, and allene-to-conjugated diene isomerization

A tandem three stages process to a series of trifluoromethyl and halodifluoromethyl 2,4-unsaturated ketones 4a-c is described. This process started with the preparation of 2-fluoroalkyl substituted propargyl vinyl ether 3a-d by treatment of a mixture of individual ethyl α-per(poly)fluoroalkyl acetates 1a-d and propargyl alcohol 2 in CH₂Cl₂ with the mixed base (Na₂CO₃/TEA) at ambient temperature. When heated in toluene at 80°C, these ethers readily underwent a tandem propargyl-allenyl Claisen rearrangement and isomerization of the resultant 3,4-dienone to give 2,4-unsaturated fluoroalkyl ketones 4a-c (Z/E mixture). The reaction of ethyl α-per(poly)fluoroalkyl acetate 1 with 1-phenyl propargyl alcohol 5 in refluxing CH₂Cl₂ in the presence of the mixed base (Na₂CO₃/TEA) directly afforded the corresponding unsaturated fluoroalkyl ketone 6a-c in one pot. In the presence of NaH, the reaction of ethyl 3-halo-3-fluoroalkylacrylates 8a-b with 1,1-dimethyl propargyl alcohol 9 at −50°C to 0°C also gave the unsaturated fluoroalkyl ketones 10a-b in one pot. The difluorovinyl propargyl ether 11 produced by reduction of 2-bromodifluoromethyl substituted propargyl vinyl ether 3b rearranged in hot benzene to give the corresponding allene 12 bearing a gem-difluoromethylene group in the middle of the aliphatic chain.     

Copper-catalyzed dehydrogenative cross-coupling reaction between unactivated ethers and simple ketones mediated by pyrrolidine

A copper-catalyzed dehydrogenative cross-coupling reaction between unactivated ethers and simple ketones mediated by pyrrolidine has been developed. Under the catalysis of CuBr₂ and in the presence of pyrrolidine, either tetrahydrofuran 2a or tetrahydropyran 2b can react smoothly with a series of methyl aryl ketones 1a–m to give desired coupling products 3aa–mb using TBHP as an oxidant. The advantages of the dehydrogenative cross-coupling reaction are adoption of unmodified ethers as substrates, good tolerance of many functional groups and use of cheap copper salt as a catalyst. A plausible radical mechanism through enamine attack is proposed.     

C11H12 Hydrocarbons—II : Preparation of tricyclo[5.4.0.0]undeca-3,8,10-triene a norbornenone route from cycloheptatriene

A stereoselective 6-step synthesis of the C₁₁H₁₂ hydrocarbon cis,anti,cis-tricyclo[5.4.0.0^2,5]undeca-3,8,10-triene (2a) is described. The dichloro compound 3c was prepared by the selective reduction of 3a with chromous perchlorate-ethylenediamine complex, a general reagent for this type of transformation. Irradiation of 3c produced 6a and 7a in ∼ 7:1 ratio. Reduction of the mixture with sodium produced ketal mixture 6b and 7b. The ketals were hydrolyzed to ketones 6c and 7c and the ketones decarbonylated to 2a and an isomeric hydrocarbon tentatively assigned as homobasketene 2b′. Hydrocarbon 2a was readily obtained pure by a silver nitrate extraction procedure and 2b′ by preparative VPC. It was shown that pure 6c gives only 2a and therefore, 7c is the source of 2b′. The stereochemical assignments, based on both spectral and chemical evidence, are discussed.     

Lewis acid-promoted reactions of ethenetricarboxylates with γ-CF3-substituted propargyl alcohols

The Lewis acid-promoted reaction of an ethenetricarboxylate derivative (1) with CF₃-substituted propargyl alcohols has been examined. Reaction of γ-CF₃ propargyl alcohols in the presence of zinc bromide gave five-membered CF₃-containing tetrahydrofurans in 66-85% yield. The CF₃ group activates alkyne as an electron-withdrawing group. On the other hand, reaction of γ-trifluoromethyl-α-aryl propargyl alcohols 2 with 1 in the presence of 1 equiv of SnCl₄ gave cyclobutane derivatives 6 in 29-49% yield. Formation of cyclobutane 6a arises from the [2+2] cycloaddition between ethenetricarboxylate 1 and chloroallene 8, which is produced by the reaction of propargyl alcohol 2a and SnCl₄.     

ClickEnam. 1. Synthesis of novel 1,4-disubsituted-[1,2,3]-triazole-derived β-aminovinyl trifluoromethylated ketones and their copper(II) complexes

The copper(I) catalyzed cycloaddition reaction of N-Boc propargyl amine (dipolarophile) 1 with benzyl azide (1,3-dipole) 2 was found to proceed smoothly in t-BuOH/H₂O at room temperature, to furnish the corresponding 1,4-disubstituted-[1,2,3]-triazole-derived N-Boc amine 3 in good yield. Deprotection of 3 with trifluoroacetic acid and addition of the trifluoroacetate salt 4 in the presence of triethylamine, with a series of methoxyvinyl(trifluoromethyl)ketones 10-14, gave the corresponding β-aminovinyl trifluoromethylated ketones 15-19 in moderate to good yields. Two copper(II) complexes, one monomer and one dimer with chlorine double bridge, 20 and 21, respectively, were also prepared and their crystal structure determined. β-Aminovinyl trifluoromethylated ketones 15-17 and complexes 20 and 21 have been screened as potential antifungal agents and the antimalarial activity of 15 and 16 were tested against two Plasmodium falciparum strains (3D7 and W2).     

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.     

The iron(III) chloride-mediated 1,4-addition of mercaptans to α,β-unsaturated ketones and esters under solvent free conditions

The 1,4-addition of various thiols to α,β-unsaturated ketones was completed rapidly in the presence of a catalytic amount (2-3 mol %) of anhydrous iron(III) chloride under solvent free conditions and an air atmosphere. Anhydrous iron(III) chloride is more active than that of other ferric salts. With more reactive and/or less steric reagents (1a-c and/or 2a-2c), expeditious conditions (short reaction times at room temperature) could be employed. With less reactive and/or steric reagents (1d-g and/or 2d-e), a slight increase in reaction time was required, but high yields were obtained. The FeCl₃ catalyst causes preferential interactions with α,β-unsaturated ketones present in the reaction.     

Synthetic studies towards complex diterpenoids—VI : New synthetic routes to tetracyclic bridged-bicyclo[3.2.1]octane intermediates by intramolecular alkylation reactions through α-diazomethyl ketones of hydroaromatic γ,δ-unsaturated acids

Two new synthetic routes to a number of tetracyclic intermediates, for the total synthesis of some diterpenoids incorporating the bicyclo[3.2.1]octane moiety, are described. The syntheses of the bicyclo[3,2,1]octane derivatives begin with preparation of the hydroaromatic γ,δ-unsaturated acids 6, 15 and 17, and proceed via the α-diazomethyl ketones to the corresponding pentacyclic ketones 20, 24 and 26 by an intramolecular carbenoid insertion reaction, followed by a regiospecific acid-catalysed cleavage of the aromatic conjugated cyclopropane bond to the respective unsaturated ketones 27, 29 and 30. The second route to these unsaturated ketones involves a single step boron trifluoride etherate catalysed intramolecular alkylation in the corresponding α-diazomethyl ketones. The tetracyclic ketones 31, 34 and 35 were obtained in quantitative yields by a regiostereospecific hydrogenolytic cleavage of the aromatic conjugated cyclopropane bond in the respective pentacyclic precursors with PdC in ethanol. Under the same conditions, reduction of the styrenoid bond in the ketones 29 and 30 proceeds stereospecifically leading to 34 and 35 respectively, whereas the unsaturated ketone 27 gave a mixture of epimeric ketones 31 and 32 in a ratio of 69:31.     

Novel catalytic hydrogenolysis of silyl enol ethers by the use of acidic ruthenium dihydrogen complexes

Treatment of 1-trimethylsilyloxy-1-cyclohexene (1a) in the presence of a catalytic amount of the acidic dihydrogen complex [RuCl(η²-H₂)(dppe)₂]OTf (4a) [dppe=1,2-bis(diphenylphosphino)ethane, OTf=OSO₂CF₃] (10 mol.%) under 1 atm of H₂ in anhydrous ClCD₂CD₂Cl at 50 °C for 8 h afforded cyclohexanone (3a) and Me₃SiH in quantitative NMR yields. Silyl enol ethers such as 1-triethylsilyloxy-1-cyclohexene (1b), 1-t-butyldimethylsilyloxy-1-cyclohexene (1c), and other trimethylsilylethers (1d, 1e, and 1f) reacted similarly with H₂ to afford the corresponding ketones and trialkylsilanes. The direct proton transfer from H₂ to the trimethylsilyl enol ethers (1a and 1d-1f) was confirmed by the experiments employing D₂ gas, where α-monodeuterated ketones (3a′ and 3d′-3f′) were obtained in high yields. The enantioselective protonation of prochiral silyl enol ethers with 1 atm of H₂ by employing [RuCl(η²-H₂)((S)-BINAP)₂]OTf (4e) [BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl] and [RuCl(η²-H₂)((R, R)-CHIRAPHOS)₂]OTf (4f) [CHIRAPHOS=2,3-bis(diphenylphosphino)butane] showed that no enantioselectivity was observed in either catalytic or stoichiometric protonation reactions under various reaction conditions. The reaction of [RuHCl(dppe)₂] (5a) with one equivalent of Me₃SiOTf under 1 atm of H₂ produced rapidly 4a, concurrent with the formation of Me₃SiH. Based on these studies, the mechanism for this novel hydrogenolysis of silyl enol ethers is proposed which involves heterolytic cleavage of the coordinated H₂ on the ruthenium atom caused by the nucleophilic attack of the oxygen atom of enol ethers to give ketones and Me₃SiOTf, and the subsequent reaction of the resultant complex 5a with Me₃SiOTf under 1 atm of H₂ to regenerate the original dihydrogen complex 4a. On the other hand, the stoichiometric reaction of a lithium enolate 6e with one equivalent of 4e at −78 °C in CH₂Cl₂ under 1 atm of H₂ afforded 2-methyl-1-tetralone (3e) with 75% ee (S) in >95% yield, together with the formation of [RuHCl((S)-BINAP)₂] (5e).     

Synthesis and substitution reactions of β-alkoxyvinyl bromodifluoromethyl ketones

β-Alkoxyvinyl bromodifluoromethyl ketones 1a, 1b and 1c were synthesized by the reaction of bromodifluoroacetic anhydride with appropriate vinyl ethers in high yields. The acyclic enone 1a reacted with amines to give the corresponding β-aminovinyl bromodifluoromethyl ketones 2 in good yields. The reaction of 1a with electrophilic reagent ICl yielded α-iodoenone 4. The substitution reaction of the cyclic enones 1b and 1c with thio-nucleophiles gave the corresponding difluoromethylene thioethers 6. The three-component reactions of 2 with primary amines and formaldehyde gave multifunctional 1,2,3,4-tetrahydropyrimidine 3 in moderate yields.     

From ketones, aldehydes or alkyl halides to terminal 1,1-difluoroolefins using BrF3

Terminal difluoromethylenes were prepared by two different routes: (a) by treating ketones and aldehydes with bis(methylthio)methane, producing 2-alkyl-1,1-bis(methylthio)alkene (2) (b) reacting alkyl halides with tris(methylthio)methane forming 1-alkyl-1,1,1-tris(methylthio)alkane derivatives (7). The reaction of either 2 or 7 with BrF₃, followed by oxidation with HOF·CH₃CN gave the difluorosulfonyl derivatives 4. Consecutive treatment with Zn led to the target difluoroolefins (5) in overall yields of 60-75%.     

Novel dinuclear iron(0) complexes from α,β-unsaturated ketones β-positioned with sulfide and sulfoxide groups

The reaction of Fe₂(CO)₉ with α,β-unsaturated ketones analogues containing β-positioned sulfoxide group 2a-2d afforded dinuclear Fe(0) complexes 3a-3d and 5 which were characterized by IR, mass spectrometry, ¹H and ¹³C NMR spectroscopy, the structures of 3a, 3c and 5 were established by X-ray diffraction analysis.     

Michael addition of chiral formaldehyde N,N-dialkylhydrazones to activated cyclic alkenes

The nucleophilic conjugate addition of chiral formaldehyde N,N-dialkylhydrazones 1 to doubly activated cyclic alkenes 2-8 proceeds smoothly to afford the corresponding Michael adducts 14, 16, 18, 20, 22, 24, and 25 in variable yields and selectivities. The reactions take place either spontaneously or in the presence of MgI₂ as a mild Lewis acid depending on the type of substrate. Release of the chiral auxiliary was achieved by transformation of the hydrazone moiety into acetals, dithioacetals or nitriles.     

Total synthesis of apigenin 7,4′-di-O-β-glucopyranoside, a component of blue flower pigment of Salvia patens, and seven chiral analogues

We have succeeded in the first total synthesis of apigenin 7,4′-di-O-β-d-glucopyranoside (1a), a component of blue pigment, protodelphin, from naringenin (2). Glycosylation of 2 according to Koenigs-Knorr reaction provided a monoglucoside 4a in 80% yield, and this was followed by DDQ oxidation to give apigenin 7-O-glucoside (12a). Further glycosylation of 4′-OH of 12a with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl fluoride (5a) was achieved using a Lewis acid-and-base promotion system (BF₃·Et₂O, 2,6-di-tert-butyl-4-methylpyridine, and 1,1,3,3-tetramethylguanidine) in 70% yield, and subsequent deprotection produced 1a. Synthesis of three other chiral isomers of 1a, with replacement of d-glucose at 7 and/or 4′-OH by l-glucose (1b-d), and four chiral isomers of apigenin 7-O-β-glucosides (6a,b) and 4′-O-β-glucosides (7a,b) also proved possible.     

The synthesis of R-3-alkoxy-1-(1′-hydroxyethyl)-4-methoxy-2-(1″-propenyl)benzenes utilizing Corey-Bakshi-Shibata asymmetric reductions

Pyrolysis of the 3-O-allyl derivative 7 of isovanillin followed by alkylation of the derived allylphenol 8 afforded a series of benzaldehyde derivatives 9-11 each of which was transformed by initial treatment with methylmagnesium bromide followed by oxidation of the corresponding alcohols with activated manganese dioxide into a series of ketones 15-17. Palladium(0) catalysed isomerization of the double bond in the prop-2′-enyl side-chain afforded ketones 36-38 which were subjected to the Corey-Bakshi-Shibata asymmetric reduction protocol to afford the R-3-alkoxy-1-(1′-hydroxyethyl)-4-methoxy-2-(1″-propenyl) benzenes 42-44 in yields of approximately 60% and with ee's of 75%.     

A one-pot, two step synthesis of 2,2-disubstituted 1-nitroalkenes

The reactions of ketones 1a-o, nitromethane 2, and a stoichiometric amount of piperidine 3a or ethylenediamine 3b in the presence of mercaptan 6a in THF or CH₃CN solution give high yields of β-nitrosulfides 7a-o. The latter can be oxidized by 8a (m-CPBA or m-CPBA/AcOH) at 0°C, 8b (H₂O₂/AcOH), or 8c (H₂O₂) at room temperature, thus generating β-nitroalkylsulfoxides 9a-o, which then undergo elimination to produce medium to high yields of 2,2-disubstituted-1-nitroalkenes 5a-o, when refluxed in a solution of ClCH₂CH₂Cl (1,2-dichloroethane). After preparation from 1a-o, 2, 3, and 6a, 7a-o were oxidized with 8a, 8b, or 8c in a mixture of CH₃CN and ClCH₂CH₂Cl to generate β-nitrosulfoxides 9a-o, which then underwent elimination under refluxing under one-pot conditions. Compounds 14 and 15g were also prepared using 13, 2, 3b, and 6, in a similar manner.     

A direct synthesis of α-(hydroxymethyl) and α-alkyl-vinyl alkyl ketones

Reaction of 2,4-diketoesters 3a-c with aqueous formaldehyde using potassium carbonate solution as base affords the corresponding α-methylene-β-hydroxyalkanones 4a-c which provide a route to α,β-unsaturated alkyl ketones 6a-e via coupling of α-acetoxymethyl alkyl vinyl ketone 5a with Grignard reagents in the presence of a catalytic amount of LiCuBr₂ at low temperature.