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.     

Synthesis of 2-substituted benzofurans and indoles using functionalized titanium benzylidene reagents on solid phase

Titanium(IV) benzylidenes bearing a masked oxygen or nitrogen nucleophile in the ortho position were generated from thioacetals, using low-valent titanocene complex, Cp2Ti[P(OEt)3]2. Methylene acetal, alkyl ether, silyl ether, fluoro, tertiary amino, and N-alkyl, N-benzyl, N-prenyl, and N-silyl tert-butyl carbamate groups were tolerated in the titanium alkylidene reagents (Schrock carbenes). Aryl-chlorine bonds were stable to the titanium benzylidene functionality, but there was poor chemoselectivity for the reduction of the thioacetal in the presence of an aryl chloride. The titanium benzylidenes converted Merrifield and Wang resin-bound esters into enol ethers. The oxygen nucleophile was masked as a TMS ether, and when the resin-bound enol ethers bearing this ortho substituent were treated with 1% TFA in dichloromethane, benzofurans were released from resin in high yields. The chameleon catch strategy ensured excellent purity. In a similar way, N-alkylated and N-silylated tert-butyl carbamates were used for the synthesis of N-alkyl and N-Boc indoles, respectively. These traceless solid-phase syntheses of heterocycles are believed to involve postcleavage modification rather than cyclative termination.     

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.     

Stereoselective synthesis of cycloheptanone derivatives via an intermolecular [5 + 2] cycloaddition reaction

[reaction: see text] A [5 + 2] cycloaddition reaction of a new five-carbon unit was developed on the basis of a dicobalt hexacarbonyl propargyl cation species. Under the influence of EtAlCl(2), [5-benzoyloxy-2-(triisopropylsiloxy)-1-penten-3-yne)]dicobalt hexacarbonyl reacted with enol triisopropylsilyl ethers to yield seven-membered dicobalt acetylene complexes in good yield. The reactions with cyclic enol silyl ethers as well as acyclic enol silyl ethers exhibited remarkably high diastereoselectivity. The cycloadducts can be easily converted into various kinds of cycloheptanone derivatives.     

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.     

W(CO)5-amine catalyzed exo- and endo-selective cyclizations of omega-alkynyl silyl enol ethers: a highly useful method for the construction of polycyclic compounds

[reaction: see text] A highly useful method for the construction of polycyclic compounds based on the amine-controlled exo- and endo-selective cyclizations of omega-alkynyl silyl enol ethers catalyzed by W(CO)5L is reported. When bis-alkynyl silyl enol ethers were treated with a catalytic amount of W(CO)6, DABCO, and water under photoirradiation, synthetically useful tricyclic ketones were obtained in good yield.     

Radical cation salts induced domino reaction of anilines with enol ethers:Synthesis of 1,2,3,4-tetrahydroquinoline derivatives

A domino reaction of anilines with cyclic and acyclic enol ethers induced by catalytic amounts of TBPA^·+（5 mol%） was investigated and a series of 2,4-disubstituted-1,2,3,4-tetrahydroquinolines were synthesized.Different from cyclic enol ethers, when acyclic enol ethers were used in the reaction,they serve as surrogates of acetaldehyde,producing a series of 2-methyl-4- anilino-1,2,3,4-tetrahydroquinolines.A single electron transfer mechanism was proposed to rationalize the products formation.     

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.     

Regioselective Synthesis of 4-Acetyl-and 5-Acetyl-3-methylisoxazole: Their Conversion into Silyl-and Methyl Enol Ethers

Acetonitrile oxide reacts regioselectively with 3-buten-2-one and (E)-4-methoxy-3-buten-2-one to give 5-acetyl-2 and 4-acetyl-3-methylisoxazole 3, respectively. Treatment of ketones 2 and 3 with trimethylsilyl trifluoromethanesulfonate gave the silyl enol ethers 4 and 5, whereas the methyl enol ethers 8 and 9 were obtained via elimination of methanol from the corresponding dimethyl ketals.     

W(CO)5(L)-catalyzed endo-selective cyclization of allenyl silyl enol ethers: an efficient method for the cyclopentene annulation onto alpha,beta-unsaturated ketones

[reaction: see text] Indium-mediated allenylation of alpha,beta-unsaturated ketones in the presence of tert-butyldimethylsilyl triflate and dimethyl sulfide gives 6-siloxy-1,2,5-trienes, which undergo W(CO)(5)(L)-catalyzed 5-endo cyclization to give the corresponding cyclopentene derivatives in good yield. Furthermore, this novel W(CO)(5)(L)-catalyzed cyclization of allenyl silyl enol ethers proceeds in a 6-endo manner when 5-siloxy-1,2,5-trienes are employed as a substrate. In these reactions, effective electrophilic activation of allenyl compounds for attack by silyl enol ethers is achieved using a catalytic amount of W(CO)(6).     

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.     

Oxidative Breaking of Long-Chain Acetylenic Enol Ethers of Glycerol of the Marine Sponges Raspailia pumila and of Model Compounds with Aerial Oxygen

The raspailynes (novel long-chain enol ethers of glycerol having the enol ethers double bond conjugated in sequence, to an acetylenic and an olefinic bond, isolated from the North-East-Atlantic sponges Raspailia pumila and R. ramosa) are stable under normal hydrolytic conditions for enol ethers. In contrast, when their solutions are evaporated, these lipids such as raspailyne Bl (=(?))-3-[(1Z,5Z)-(tetradeca-1,5-dien-3-ynyl)oxy]-1,2-propanediol;(?- 2 ) rapidly react with aerial O₂ under normal laboratory-daylight conditions, with rupture of the C=C enol ether bond to give 1-O-formylglycerol ( 3 ) and an aldehyde (such as tridec-4-en-2ynal( 4 ) from (?)- 2 ). This reaction must be caused by triplet O₂, since thermally generated singlet O₂ has no effect on (?)- 2 in solution. That the mere presence of an enol-ether moiety conjugated to an acetylenic group is responsible for such a behaviour is demonstrated with the model compounds 1-methoxypentadec-1-en-3-yn-5-ol ( 6a ) and its 5-O-acetyl or 5-O-tetra-hydropyranyl derivatives 6b and 6c , respectively. Resistance to both hydroytic conditions and singlet O₂ of these compounds is thought to arise from electron depletion at the enol-ether C(beta;) atom by the acetylenic group. Plausible reaction pathways for enol-ether bond rupture in these compounds by aerial O₂ are outlined.     

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.     

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.     

Cycloaddition reaction of 2-azadienes derived from beta-amino acids with electron-rich and electron-deficient alkenes and carbonyl compounds. Synthesis of pyridine and 1,3-oxazine derivatives

Functionalized keto-enamines 6 were obtained by nucleophilic addition of enol ethers to the imine moiety of 2-azadienes derived from dehydroaspartic esters 4. Reactions of 2-azadiene 4c containing three electron-withdrawing substituents (CO(2)R) with enol ethers 5 in the presence of lithium perchlorate led to the formation of tetrahydropyridine derivatives 7 in a regio- and stereoselective fashion. 2H-[1,3]-oxazines 10 and pyridine derivatives 12 and 13 were obtained by heterocycloaddition reactions of electron-poor azadienes 4d-g containing two electron-withdrawing substituents (4-O(2)N-C(6)H(4), CO(2)R) in positions 1 and 4 with carbonyl derivatives (ethyl glyoxalate 9a and diethyl ketomalonate 9b) and the electron-deficient olefin tetracyanoethylene 11.     

Simultaneous construction of a polyether backbone and a variety of keto side chains by three‐component polycondensation: An improved method for the use of a variety of silyl enol ethers

For the synthesis of polyethers with a variety of keto side chains in a one‐step reaction, the three‐component polycondensation of dialdehydes, diol disilyl ethers, and silyl enol ethers of ketones was investigated. The method of monomer addition strongly affected the molecular weight of polymers and was optimized to yield high molecular weight polymers by model reactions. A variety of dialdehydes, diol disilyl ethers, and silyl enol ethers were polymerized in the presence of a catalytic amount of triphenylmethyl (trityl) perchlorate in CH₂Cl₂ at −78 °C according to the method of monomer addition. This polymer synthesis was unusual in that it concurrently constructed both the polyether backbone and the keto side chains from three starting compounds. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 179–188, 2000     

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     

Scope and limitations of chiral B-

A new chiral oxazaborolidine catalyst was prepared in situ from 3, 5-bis(trifluoromethyl)phenylboron dichloride and N-(p-toluenesulfonyl)-(S)-tryptophan. This catalyst is much more active than Corey's original catalyst for the Mukaiyama aldol reaction of aldehydes with silyl enol ethers. The observed syn selectivities and re-face attack of silyl enol ethers on carbonyl carbon of aldehydes imply that the extended-transition state model is applicable.     

Direct Formylation of Enol Ethers Using Cyanuric Chloride and N,N‐Dimethylformamide

A new method to prepare α,β‐unsaturated enol aldehydes is described. 3‐Ethoxymethacrolein ( 1 ) and 5‐formyl‐3,4‐dihydro‐2H‐pyran ( 5 ) were effectively prepared from enol ethers and the Vilsmeier‐Haack type complex, derived from cyanuric chloride and DMF. One byproduct, amidine 4 , was also characterized.     

Haloacetylated enol ethers. 5 [5]. Heterocyclic ring closure reactions of β-alkoxyvinyl dichloromethyl ketones with hydroxylamine

The β-alkoxyvinyl dichloromethyl ketones 1a-d are cyclocondensed with hydroxylamine hydrochloride in pyridine to afford the 5-hydroxy-5-dichloromethyl-4,5-dihydroisoxazoles 2a-d in good yield. The cyclo-condensation of compound 1c gave, together with 2c , 3-cyano-2-hydroxy-2-dichloromethyltetrahydrofuran 5c. The dehydratation of compounds 2a,b , derived from acyclic enol ethers, with concentrated sulfuric acid at 30°, led the corresponding 5-dichloromethylisoxazoles 3a,b. The dehydratation of compounds 2c,d , derived from cyclic enol ethers, with concentrated sulfuric acid at 30°, led the bicyclic 4,5-dihydroisoxazoles 4c,d , and at 55°, a competitive rearrangement reaction gives the 3-cyano-2-hydroxy-2-dichloromethyl-2H-pyran 5d.