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).     

Tandem Parham cyclisation--α-amidoalkylation reaction in the synthesis of the isoindolo[1,2-a]isoquinoline skeleton of nuevamine-type alkaloids

C-12b substituted isoindolo[1,2-a]isoquinolones 4 are prepared efficiently via a tandem Parham cyclisation--α-amidoalkylation reaction. Thus, Parham cyclisation on imide 1 generates a 12b-hydroxy isoindolo[1,2-a]isoquinolone, which is an immediate precursor of an N-acyliminium ion. Intermolecular alkylation with different π-nucleophiles (allyl silanes or enol ethers) is accomplished upon treatment with Lewis acids (BF₃·OEt₂, TiCl₄) to obtain nuevamine-type derivatives in high yields (69-95%) under mild conditions.     

Asymmetric formal synthesis of (−)-pancracine via catalytic enantioselective C-H amination process

The reaction of silyl enol ethers derived from cyclohexanone with [(4-nitrophenylsulfonyl)imino]phenyliodinane (pNsNIPh) catalyzed by dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh₂(S-TCPTTL)₄, provides, after desilylation, N-pNs-protected (S)-β-aminocyclohexanone in up to 72% ee. This represents the first example of the insertion of nitrene species into an allylic C-H bond of silyl enol ethers. Using this process, a new catalytic asymmetric route to an advanced intermediate in Overman's synthesis of the montanine-type Amaryllidaceae alkaloid (−)-pancracine has been developed. The key steps involve (a) a one-pot Rh₂(R-TCPTTL)₄-catalyzed sequential 1,4-hydrosilylation/enantioselective C-H amination of 2-cyclohexen-1-one, (b) N-alkylation and subsequent intramolecular Mukaiyama aldol reaction/dehydration, and (c) a regio- and stereocontrolled reductive deoxygenation of bicyclic enone 27 with migration of the double bond to create the C1/C11a double bond and the stereogenic center at C11 of 3-arylhexahydroindole 31.     

Application of the Gould-Jacobs reaction to 4-amino-2,1,3-benzoselenadiazole

An effective method for the synthesis of 4-amino-2,1,3-benzoselenadiazole (4) has been described. Reduction of readily available 4-nitrobenzothiadiazole 6 with SnCl₂·2H₂O afforded 1,2,3-triaminobenzene dihydrochloride 2. The latter upon treatment with aqueous SeO₂ solution provided desired amine 4. Nucleophilic vinylic substitution of activated enol ethers 7 with amine 4 led to (benzoselenadiazol-4-ylamino)methylene derivatives 8. Thermal cyclization of derivatives 8a-c, e, f under Gould-Jacobs reaction conditions gave angularly annelated 7-(non)substituted selenadiazolo[3,4-h]quinolones 9. Acid hydrolysis of etyl ester 9c afforded corresponding acid 10. All prepared selenadiazoloquinolones were tested for antimicrobial activity.     

Copper-catalyzed oxidative cleavage of carbon-carbon double bond of enol ethers with molecular oxygen

A novel CC bond cleavage reaction of aromatic enol ethers (1) to give ketones (2) using molecular oxygen as oxidant is described. Among the examined catalysts (Cu(II), Pd(II), Ru(II), and H⁺), CuCl₂ exhibited the highest activity. The reaction proceeded smoothly with several kinds of substrates.     

Asymmetric Mukaiyama aldol reaction of silyl enol ethers with aldehydes using a polymer-supported chiral Lewis acid catalyst

Chiral N-sulfonylated α-amino acid monomer (5) derived from (S)-tryptophan was copolymerized with styrene and divinylbenzene under radical polymerization conditions to give a polymer-supported N-sulfonyl-(S)-tryptophan (6). Treatment of the polymer-supported chiral ligand with 3,5-bis(trifluoromethyl)phenyl boron dichloride afforded a polymeric Lewis acid catalyst (16) effective for asymmetric Mukaiyama aldol reaction of silyl enol ethers and aldehydes. Various aldehydes were allowed to react with silyl enol ethers in the presence of the polymeric chiral Lewis acid to give the corresponding aldol adducts in high yield with high levels of enantioselectivity.     

1-Phenylthio-3-vinyl-3-cyclohexenol, a new reagent for bis-annelation of silyl enol ethers

1-Phenylthio-3-vinyl-cyclohex-1-en-3-ol (2) has been synthesized and investigated as a new bis-annelation reagent for silyl enol ethers. Reagent 2 can be synthesized by a Grignard reaction of vinyl magnesium bromide with 3-phenylthiocyclohexenone. The reaction with silyl enol ethers takes place under Lewis acid catalysis and generally proceeds in good yields. The resulting phenylthiodienes can be hydrolyzed to enones, which have been cyclized in a homologous aldol reaction to polycyclic compounds.     

Synthesis of (2S,3R)- and (2S,3S)-[3-H1]-proline via highly stereoselective hydrolysis of a silyl enol ether

A straightforward synthesis of (2S)-[3,3-²H₂]-proline 1c and (2S,3R)- and (2S,3S)-[3-²H₁]-proline, 1b and 1a, respectively, has been devised. The key step of the route to the latter compounds involves highly stereoselective hydrolysis of the silyl enol ethers 3 and 3a, respectively, with protonation (deuteriation) from the re-face of the silyl enol ether.     

BF3·Et2O catalyzed diastereoselective nucleophilic reactions of 3-silyloxypiperidine N,O-acetal with silyl enol ether and application to the asymmetric synthesis of (+)-febrifugine

The asymmetric BF₃·Et₂O catalyzed nucleophilic reactions of 3-silyloxypiperidine N,O-acetal 10 with silyl enol ethers derived from ketones are described. (+)-Febrifugine 1, an antimalarial alkaloid, was successfully synthesized based on this nucleophilic substitution. In addition, N,O-acetal 10 was synthesized from l-benzyl glutamate in 11 steps.     

Preparation of 1-aryl-2,2-difluoro enol esters via dehydrosulfonylation of α-(phenylsulfonyl)difluoromethylated benzoates

1-Aryl-2,2-difluoro enol benzoates 4 has been prepared from α-(phenylsulfonyl)-difluoromethylated benzoates 3, which can be readily obtained from the reactions between simple aldehydes and PhSO₂CF₂H (or TMSCF₂SO₂Ph). 2,2-Difluoro enol esters 4 are relatively more stable compounds than 2,2-difluoro enol sily ethers, and they promise to act as interesting fluorinated building blocks for further elaborations.     

Asymmetric Michael addition of silyl nitronates to cyclic α,β-unsaturated ketones catalyzed by chiral quaternary ammonium bifluorides: isolation and selective functionalization of enol silyl ethers of optically active γ-nitro ketones

Highly enantioselective Michael addition of silyl nitronates to cyclic α,β-unsaturated ketones has been accomplished by the utilization of N-spiro C₂-symmetric chiral quaternary ammonium bifluoride 1 as an efficient catalyst, offering a new route to the enol silyl ethers of optically active γ-nitro ketones. The synthetic utility of this transformation has been demonstrated by the diastereoselective derivatizations of the optically active enol silyl ethers to the corresponding α-substituted cyclic ketones having three consecutive stereochemically defined stereocenters.     

The synthesis, Na+ binding properties of new coumarin-crown ethers

o-Dihydroxy-3-(methylphenyl)-chromenones (coumarins; 3a–3c) were synthesized from trimethoxybenzaldehydes through a reaction with the corresponding methylphenyl-acrylonitrile in pyridine·HCl and then H₃O⁺. Dihydroxycoumarins reacted with the ditosylate or dichloride derivatives of tri- or tetraethyleneglycols in the presence of CH₃CN/Na₂CO₃ and macrocyclic ethers with a coumarin moiety were obtained. The chromatographically purified new coumarin-crown ethers (5a–5f) were identified by IR, ¹H NMR, and Mass spectrometry. The binding constants of Na⁺ with the coumarin-crown ethers were determined in an 80 % dioxane/water binary solvent system at 25 °C from conductance measurements.     

Addition of carbon nucleophiles to cyclic N-acyliminium ions in SDS/water

The acid-catalyzed addition of 1,3-dicarbonyl compounds and activated olefins (silyl enol ethers and ethyl vinyl ether) to N-Boc-2-methoxypyrrolidine (1a) and N-Boc-2-methoxypiperidine (1b) in SDS/water medium is described. Good yields of the corresponding 2-substituted N-Boc pyrrolidines were generally observed from 1a while moderate yields prevailed from 1b.     

Iron(III) Tosylate in the Preparation of Dimethyl and Diethyl Acetals from Ketones and β -Keto Enol Ethers from Cyclic β -Diketones

An efficient method for conversion of ketones to their corresponding dimethyl and diethyl acetals and of cyclic β-diketones into β-keto enol ethers using Fe(OTs)₃ as a catalyst is described.     

Reaction Equilibrium and Kinetics of Synthesis of Polyoxymethylene Dimethyl Ethers from Formaldehyde and Methanol

Polyoxymethylene dimethyl ethers (PODE _n ) are environmentally friendly diesel fuel additives. They belong to alkyl ethers that could reduce solid particulate matter formation and emissions of carbon monoxide and nitrogen oxide when added into diesel fuels. This work aimed to researching chemical equilibrium and reaction kinetics of the synthesis of polyoxymethylene dimethyl ethers from formaldehyde and methanol catalyzed by an ion-exchange resin at the reaction temperatures 313, 333, 343 and 353 K. In the reversible reaction, the K_{n ≥ 2}/K₂ ratio was equal to one. The reaction orders of methanol, formaldehyde, water and PODE _n were 0.2638, 0.1328, 0.1565 and 0.0048, respectively. At a 10 wt % dosage of H-SIR1 resin, the rate constants of the methylal (dimethoxymethane) formation and depolymerization were 1.04 × 10⁴ and 3.43 × 10⁶ min^–1, respectively, and the pre-exponential factor for the PODE_{n + 1} formation was 2.50 × 10³ min^–1. Activation energies for the methylal propagation and depolymerization and PODE_{n > 1} formation were 30.46, 48.40 and 27.10 kJ/mol, respectively. The results indicated that the equilibrium constants of PODE_{n > 1} formation reactions were consistent. The exothermic reaction of methylal formation was easier than the reverse reaction and more difficult than the formation of PODE_{n > 1}.     

Symmetrical Ketones from Aldehyde Trimethylsilyl Enol Ethers on Storage: A Cautionary Note

The widespread use of trialkylsilyl enol ethers has dramatically increased the utility of enolate anion chemistry.¹ These enol ethers are readily prepared, reactive, and in many instances are stable enough to be commercially available. We have been using trimethylsilyl enol ethers as aldehyde enolate precursors and wish to report some observations regarding storage of these 1-alkyl-2-trimethylsilyloxyethenes. We have noted that after 2–3 months in sealed glass ampuoles these trimethylsilyl enol ethers contained significant amounts of symmetrical ketones.     

Reaction behavior of cyclopropylmethyl cations derived 1-phenylselenocyclopropylmethanols with acids

The 1-phenylselenocyclopropylmethyl cations are generated by the reaction of the corresponding cyclopropylmethanols 1 with TsOH. The reaction in methanol proceeds to afford the homoallylic ethers 2, ring-enlargement products 3, 4, and ring opening products 5 depending upon the kind of substituent on the cyclopropane ring or the α-carbon. On the other hand, in the case of the absence of methanol as nucleophile, 4H-selenochromene derivative 7 is obtained exclusively. The oxidative elimination of the phenylselenyl group in the resulting phenylselenohomoallylic compounds 2 furnishes functionalized allene derivatives and alkyne derivatives.     

Testosterone Heptafluorobutyrates: Derivatives for Gas Chromatography

Abstract

The reaction of testosterone with heptafluorobutyric anhydride, in the presence of pyridine or collidine, leads to two diheptafluorobutyrate (HFB) derivatives. These compounds are believed to be the di-HFB esters of 2,4-androstadien-3, 17β-diol (A) and 3, 5-androstadien-3, 17β-diol (B), with A as the major product. This is similar to the reaction with silylating reagents which leads to two isomeric enol ethers. In benzene or acetone solution, and in the absence of an organic base, the same two isomers are formed, but with B as the major product. Although the latter reaction has been recommended for quantitative work, the formation of isomeric enol esters has not been noted. Since the products are not stable in the reaction medium, the method is not entirely satisfactory. The reaction in pyridine solution should be suitable for quantitative work; the products are stable in solution and can be detected in subnanogram amounts.     

Mucohalic acid in Lewis acid catalyzed Mukaiyama aldol reaction: a concise method for highly functionalized γ-substituted γ-butenolides

The first Mukaiyama aldol reaction on mucohalic acid (1a/b) has been achieved. Reaction of 1 with various ketene silyl acetals or silyl enol ethers in the presence of a Lewis acid provides the γ-substituted γ-butenolides in good to excellent yield.