Titanium reagents for the synthesis of 2-substituted benzo[b]thiophenes on the solid phase

Titanium(IV) benzylidenes (Schrock carbenes) bearing a masked sulfur nucleophile in the ortho position were generated from thioacetals with use of low-valent titanocene complex Cp(2)Ti[P(OEt)(3)](2) and alkylidenated Merrifield resin-bound esters to give enol ethers. Treatment of the resin-bound enol ethers with a 5:5:90 mixture of TFA, TFAA, and dichloromethane led to cleavage from resin, removal of the tert-butyldimethylsilyl (TBDMS) protecting group, and concomitant cyclization to complete the traceless solid-phase synthesis (SPS) of benzothiophenes. Switching the nature of the linker from acid-stable to acid-sensitive ensured good purity.     

Boronate titanium alkylidene reagents for diversity-based synthesis of benzofurans

[reaction: see text] Novel titanium benzylidenes (Schrock carbenes) bearing an arylboronate group are generated from thioacetals with low valent titanium species, Cp(2)Ti[P(OEt)(3)](2), and alkylidenate Merrifield resin-bound esters to give enol ethers. Treatment with 1% TFA gives 2-substituted (benzo[b]furan-5-yl)boronates, and solid-phase Suzuki cross-coupling gives 2,5-disubstituted benzofurans. Steps in the syntheses of thioacetal substrates include selective lithiation-boronation, hydrolysis of a MOM group without affecting a boronate ester, and cross-coupling with bis(pinacolato)diboron.     

High throughput synthesis of diverse 2,5-disubstituted indoles using titanium carbenoids bearing boronate functionality

A titanium benzylidene complex bearing a boronate group converted resin-bound esters into enol ethers. Suzuki cross-coupling with aryl iodides followed by cleavage with acid completed the solid-phase synthesis of 2,5-disubstituted N-Boc-indoles. Also reported is the use of tert-butyllithium and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to convert an aryl bromide into an arylboronate in the presence of a dithiane, with simultaneous reduction of an aryl azide to an amine.     

Preparation of quinolines from resin-bound esters using titanium reagents

ortho-Amino homobenzylic thioacetals are prepared from ortho-nitrobenzaldehydes via homologation using an alpha-methoxy Wittig reagent. Titanium reagents are generated from the 1,3-dithianes using a low valent titanium reagent and are then used to alkylidenate resin-bound esters. An N-silylated Boc group protects the ortho-amino functionality. Traceless SPS of quinolines is completed by treating the resulting resin-bound enol ethers with TFA and then oxidizing with manganese dioxide to give 2-substituted quinolines in high purity without the need for chromatography.     

Anodic cyclization reactions: capitalizing on an intramolecular electron transfer to trigger the synthesis of a key tetrahydropyran building block

An anodic cyclization reaction between an enol ether radical cation and an oxygen nucleophile has been used to make a tetrahydropyran building block for the C(10)-C(16) portion of bryostatin. The oxidative cyclization was successful despite the presence of a thioacetal group that has a lower oxidation potential than the enol ether. Experimental evidence suggested that the reaction proceeded through an initial oxidation of the thioacetal followed by an intramolecular electron transfer to form the enol ether radical cation that was subsequently trapped by the oxygen nucleophile. The formation of the desired cyclic product could be explained using the Curtin-Hammett principle. By taking advantage of the intramolecular electron-transfer reaction, we used the presence of a thioacetal in an electrolysis substrate to selectively oxidize a proximal enol ether in the presence of an otherwise identical but more remote enol ether.     

Facile ring transformation from gluconolactone to cyclitol derivative via spiro sugar ortho ester

[reaction: see text] A short step preparation of cyclitol derivative 8 which is a versatile synthon for the synthesis of valiolamine and its related compounds is described. Key steps in this preparation are a novel enol ether formation from spiro sugar ortho esters with AlMe3 and an intramolecular Aldol condensation of alkyl enol ethers catalyzed by ZnCl2 in THF-H2O. With these reactions, gluconolactone derivative 1 was efficiently converted into 8 in short steps.     

Endo-oxacyclizations of polyepoxides: biomimetic synthesis of fused polycyclic ethers

Boron trifluoride-etherate promotes the endo-selective oxacyclization of polyepoxides derived from various acyclic terpenoid polyalkenes, including geraniol, farnesol, and geranylgeraniol, providing an efficient and stereoselective synthesis of substituted oxepanes and fused polyoxepanes. The mechanism of the oxacyclization reaction probably involves intramolecular nucleophilic addition of epoxide oxygen to open another epoxide that is activated as an electrophile by the Lewis acid. These oxacyclizations proceed stereospecifically with inversion of configuration upon opening of each epoxide to provide trans-fused polycyclic products. The oxacyclization cascade is terminated by a tethered nucleophile, which may be the carbonyl oxygen of a ketone, ester, or carbonate, or a trisubstituted alkene. The best oxacyclization yields are generally observed with tert-butyl carbonate as the terminating nucleophile, although in some cases the oxacyclization products include formation of tert-butyl ethers as a minor product. The oxacyclization transformations described herein may mimic ring-forming steps in the biosynthesis of trans-syn-trans-fused polycyclic ether marine natural products.     

Enantioselective Aldol Reactions Catalyzed by Chiral Phosphine Oxides

The development of enantioselective aldol reactions catalyzed by chiral phosphine oxides is described. The aldol reactions presented herein do not require the prior preparation of the masked enol ethers from carbonyl compounds as aldol donors. The reactions proceed through a trichlorosilyl enol ether intermediate, formed in situ from carbonyl compounds, which then acts as the aldol donor. Phosphine oxides activate the trichlorosilyl enol ethers to afford the aldol adducts with high stereoselectivities. This procedure was used to realize a directed cross‐aldol reaction between ketones and two types of double aldol reactions (a reaction at one/two α position(s) of a carbonyl group) with high diastereo‐ and enantioselectivities.     

Dicobalt octacarbonyl-catalyzed cationic polymerization of allylic and enolic ethers

In the presence of silanes bearing Si H groups, dicobalt octacarbonyl [Co₂(CO)₈] efficiently catalyzes the cationic polymerization of a wide variety of enol ether and other related monomers including vinyl ethers, 1-propenyl ethers, 1-butenyl ethers, 2,3-dihydrofuran, 3,4-dihydro-2H-pyran, ketene acetals, and allene ethers. In addition, this catalyst system is also effective for the polymerization of complimentary allylic and propargylic ethers by a process involving tandem isomerization and cationic polymerization. This latter process occurs by a stepwise mechanism in which the allylic or propargylic ether is first isomerized, respectively, to the corresponding enol ether or allenic ether and then this latter compound is rapidly cationically polymerized in the presence of the catalyst. In accord with this mechanism, it has been shown that the structure of the polymers prepared from related enol and allyl ethers using the above catalyst system are identical. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 1579–1591, 1997     

Intramolecular regioselective addition of radicals and carbanions to ynol ethers. A strategy for the synthesis of exocyclic enol ethers

The scope and limitations of radical and anionic cyclization reactions involving halo ynol ethers have been investigated. 5-exo and 6-exo radical cyclizations of 6-iodo and 7-iodo ynol ethers proceeded well when the oxygen of the ynol ether was bearing an ethyl group. Exocyclic iodoenol ethers resulting from these cyclizations were highly unstable and decomposed rapidly. Li-I exchange of iodo ynol ethers proceeded smoothly at −78 °C. 6-Alkoxy-5-hexynyllithiums underwent regiospecific 5-exo-dig anionic cyclization to produce five-membered rings bearing an exocyclic enol ether moiety. The cyclized vinyllithium intermediate was successfully trapped with electrophiles to afford functionalized cycloalkoxyalkylidene derivatives in modest to good yields. 7-Alkoxy-6-heptynyllithiums did not cyclize via a 6-exo anionic process.     

A new approach to c-glycoside congeners: Metal carbene mediated methylenation of aldonolactones.

Versatile intermediates for the synthesis of C-glycosides and oxygen heterocycles are readily available through titanium mediated methylenation of aldonolactones.Aldonolactones may be alkylated using the titanium carbene complex 2. The resulting enol ethers are of value as potential substrates for glycosidase enzymes. A high yield two step process for alkylation of these enol ethers was described. The products and procedures are relevant to the synthesis of mycotoxins, including citreoviridin and aurovertin B.     

A mild and efficient method for the stereoselective formation of C-O bonds: palladium-catalyzed allylic etherification using zinc(II) alkoxides

[reaction: see text] A highly chemo- and stereoselective palladium-catalyzed allylic etherification reaction is described. The use of zinc(II) alkoxides proved effective in promoting the addition of the oxygen nucleophile derived from aliphatic alcohols to eta(3)-allylpalladium complexes. Using diethylzinc (0.5 equiv), 5 mol % of Pd(OAc)(2), and 7.5 mol % of 2-di(tert-butyl)phosphinobiphenyl in THF, the cross-coupling reaction between various aliphatic alcohols and allylic acetates proceeded at ambient temperature to furnish allylic ethers with high stereoselectivity.     

Arylsulfonate-based nucleophile assisting leaving groups

[Chemical reaction: See text] The synthesis and unique reactivity of a series of arylsulfonate-based nucleophile assisting leaving groups (NALG) containing oligomeric ether units (including crown ethers) attached to the arylsulfonyl ring in the ortho orientation are described. The reactions of a variety of these ether-containing alkyl sulfonates with metal halides proceeded at substantially greater rates than electronically similar sulfonates. These ether-containing leaving groups also displayed marked selectivity for lithium halides relative to the corresponding sodium and potassium salts in nucleophilic displacement reactions.     

alpha-Nitration of Ketones via Enol Silyl Ethers. Radical Cations as Reactive Intermediates in Thermal and Photochemical Processes

Highly colored (red) solutions of various enol silyl ethers and tetranitromethane (TNM) are readily bleached to afford good yields of alpha-nitro ketones in the dark at room temperature or below. Spectral analysis show the red colors to be associated with the intermolecular 1:1 electron donor-acceptor (EDA) complexes between the enol silyl ether and TNM. The formation of similar vividly colored EDA complexes with other electron acceptors (such as chloranil, tetracyanobenzene, tetracyanoquinodimethane, etc.) readily establish enol silyl ethers to be excellent electron donors. The deliberate irradiation of the diagnostic (red) charge-transfer absorption bands of the EDA complexes of enol silyl ethers and TNM at -40 degrees C affords directly the same alpha-nitro ketones, under conditions in which the thermal reaction is too slow to compete. A common pathway is discussed in which the electron transfer from the enol silyl ether (ESE) to TNM results in the radical ion triad [ESE(*)(+), NO(2)(*), C(NO(2))(3)(-)]. A subsequent fast homolytic coupling of the cation radical of the enol silyl ether with NO(2)(*)() leads to the alpha-nitro ketones. The use of time-resolved spectroscopy and the disparate behavior of the isomeric enol silyl ethers of alpha- and beta-tetralones as well as of 2-methylcyclohexanone strongly support cation radicals (ESE(*)(+)) as the critical intermediate in thermal and photoinduced electron-transfer as described in Schemes 1 and 2, respectively.     

Quantum theory of atoms in molecules analysis on the conformational preferences of vinyl alcohol and related ethers

Vinyl alcohol, methyl vinyl ether, and tert-butyl vinyl ether were studied within the framework of the quantum theory of atoms in molecules at the B3LYP/6-311++G(2d,2p) level. Local and integrated properties of the charge density indicate that the anti conformational preference of the tert-butyl derivative is not due to a differing resonance contribution with regard to the less bulky vinyl ethers but to steric effects. There is a small delocalization of charge density, either total or pi, between oxygen and the terminal vinyl carbon, which does not support the resonance picture of vinyl compounds.     

The Ireland-Claisen rearrangement as a probe for the diastereoselectivity of nucleophilic attack on a double bond adjacent to a stereogenic centre carrying a silyl group

The E- and Z-silyl enol ethers 4 derived from allyl 3-R-3-dimethyl(phenyl)silylpropanoate (R = Me, Pr(i) and Ph) and the Z-silyl enol ethers 7 derived from 4-R-4-dimethyl(phenyl)silylbut-2-enyl acetate (R = Me and Pr(i)) undergo Ireland-Claisen rearrangements largely in the same stereochemical sense, with C-C bond formation taking place anti to the silyl group in the conformations 22, 23 and 24 in which the hydrogen atom on the stereogenic centre is inside, more or less eclipsing the double bond. The E-silyl enol ether E-7a derived from 4-methyl-4-dimethyl(phenyl)silylbut-2-enyl acetate shows low diastereoselectivity in the alternative sense, probably because C-C bond formation takes place anti to the silyl group in the conformation 26 with the methyl group inside, but the silyl enol ether E-7b derived from 4-isopropyl-4-dimethyl(phenyl)silylbut-2-enyl acetate shows low diastereoselectivity in the normal sense. The E- and Z-silyl enol ethers 33 derived from cis-crotyl 3-phenyl-3-dimethyl(phenyl)silylpropanoate and the E-silyl enol ether 39 derived from trans-crotyl 3-phenyl-3-dimethyl(phenyl)silylpropanoate undergo Ireland-Claisen rearrangements largely in the same stereochemical sense as their allyl counterparts, but with moderately high levels of diastereocontrol in setting up the third stereogenic centre following from chair-like transition structures.     

Cyclooctanone synthesis via a formal [6+2] cycloaddition reaction of a dicobalt acetylene complex

An efficient formal [6+2] cycloaddition reaction of a new six-carbon unit with enol silyl ether was developed on the basis of a dicobalt hexacarbonyl propargyl cation species. Under the influence of EtAlCl₂, 6-benzoyloxy-2-(triisopropylsilyloxy)-1-hexen-4-yne-dicobalthexacarbonyl reacted with enol triisopropylsilyl ethers to yield 7-(triisopropylsilyloxy)-3-cyclooctyn-1-one-dicobalthexacarbonyl derivatives in good yield. The reactions with cyclic enol silyl ethers as well as acyclic enol silyl ethers exhibited remarkably high diastereoselectivity.     

Simple method for the analysis of glycerol enol ethers derived from plasmalogens in complex lipid mixtures and subsequent determination of the aldehydic components by gas chromatography-mass spectrometry

Glycerol enol ethers, obtained by the reduction of plasmalogens with lithium aluminum hydride, can be converted into glycerol alk-(1)-enyl ether bismethyl ethers with diazomethane in the presence of silica gel. Their mass spectra allow the position of the enol ether group in glycerol unit to be deduced. Branches in the aldehydic components of the glycerol alk-(1)-enyl ether bismethyl ethers can be identified unequivocally by preparation of the 2-alkyl-1,3-dithiolanes, desulphurization with Raney nickel and deuterium to hydrocarbons and subsequent analysis by gas chromatography-mass spectrometry.     

Reactivity of nitrovinylquinones with cyclic and acyclic enol ethers

The nitrovinyl-substituted quinones 2-(2-nitrovinyl)-1,4-benzoquinone and 2-(2-nitrovinyl)-1,4-naphthoquinone react with a variety of cyclic and acyclic enol ethers via two competing pathways. In one pathway, the nitrovinylquinone acts as an inverse electron-demand [4 + 2] diene. This gives quinoid carbocycles, which readily tautomerize to their hydroquinone form. The other pathway involves conjugate (Michael) addition of the enol ether to the nitrovinylquinone, followed by ring closure. This gave dihydrobenzofurans, which can eliminate an alcohol to give benzofurans. Hindered enol ethers tended to favor the conjugate addition pathway, while less hindered enol ethers favored cycloaddition.     

Tandem carbocupration/oxygenation of terminal alkynes

[chemical reaction: see text]. A direct and general synthesis of alpha-branched aldehydes and their enol derivatives is described. Carbocupration of terminal alkynes and subsequent oxygenation with lithium tert-butyl peroxide generates a metallo-enolate. Trapping with various electrophiles provides alpha-branched aldehydes or stereo-defined trisubstituted enol esters or silyl ethers. The tandem carbocupration/oxygenation tolerates alkyl and silyl ethers, esters, and tertiary amines. The reaction is effective with organocopper complexes derived from primary, secondary, and tertiary Grignard reagents and from n-butyllithium.