A new method for the synthesis of mixed orthoesters from O-allyl acetals

Two new methods for the synthesis of orthoesters and compounds containing an orthoester moiety (dihydroisoxazoles) are presented. Mixed orthoesters of general formulas RC(OR¹)(OR²)₂ and RC(OR¹)(OR²)(OR³) were prepared via addition of ROH (R = Bu or m-methylphenyl) to O-allyl acetals (acrolein acetals: diethyl or cyclic, i.e., 2-vinyl-1,3-dioxanes or dioxolanes). The catalytic systems for these reactions were generated from [RuCl₂(PPh₃)₃] and Na₂CO₃; {[RuCl₂(COD)]_x} or {[OsCl₂(1,5-COD)]_x}, PPh₃, and Na₂CO₃. Compounds containing an orthoester moiety (dihydroisoxazoles) were prepared via tandem isomerization of O-allyl acetals (to O-vinyl acetals) catalyzed by ruthenium complexes followed by cycloaddition to in situ-generated 2,6-dichlorophenylnitrile oxide.     

Intramolecular electrophilic aromatic substitution of α-alkylcinnamaldehydes affording 1-alkoxy-2-alkylindenes

Treatment of α-alkylcinnamaldehydes with orthoesters, alcohols, or thiols in the presence of BF₃·OEt₂ induces an intramolecular electrophilic aromatic substitution reaction to afford 1-alkoxy-2-alkylindenes. The reaction mechanisms of the indene formation have been elucidated on the basis of the reaction behaviors of β-deuterated α-methylcinnamaldehyde and the NMR studies of the reaction mixture. The transformation process involves successive reactions, i.e., alkoxylation of the carbonyl carbon of α-alkylcinnamaldehydes to form acetals, elimination of alkoxide from the acetals to give alkoxycarbenium ion and γ-alkoxyallyl cation, and intramolecular electrophilic arylation to afford the indene ring structure.     

A simple TiCl4 promoted arylation of orthoformate and benzyl ethers by N,N-dialkylarylamines

N,N-Dialkylarylamines react with trimethyl orthoformate and TiCl₄ under ambient conditions to give the corresponding formyl derivatives in 75-89% yields, whereas the corresponding arylated products are obtained from benzyl ethers and acetals in 42-78% yields.     

Stereoselective radical cyclizations of N-(2-halobenzoyl)-cyclic ketene-N,X(X=O, S)-acetals

2-Alkyloxazolines and 2-alkylthiazolines react with 2-halobenzoyl chlorides to form N-(2-halobenzoyl)-cyclic ketene-N,O-acetals and N-(2-halobenzoyl)-cyclic ketene-N,S-acetals in excellent yields, respectively. These ketene acetals readily undergo stereocontrolled aryl radical cyclizations to afford the central six-membered rings of substituted-2,3,10,10α-tetrahydrooxazolo[3,2-b]isoquinolin-5-ones and their 2,3,10,10α-tetrahydrothiazolo[3,2-b]isoquinolin-5-one analogs. The tertiary N,O- and N,S-radicals formed upon aryl radical reaction at the ketene-N,X(X=O, S)-acetal double bond appear to have reasonable stability. The stereoselectivity in hydrogen abstractions by these intermediate radicals from both Bu₃SnH and (Me₃Si)₃SiH was investigated. The N,S-heterocyclic fused ring products may have potential medical value.     

Practical optical resolution of dl-muscone using tartaric acid derivatives as a chiral auxiliary

A simple and practical synthesis of (R)-(−)-muscone was achieved by optical resolution of dl-muscone using tartaric acid derivatives. The acetalization of dl-muscone with N,N′-dibenzyl-l-tartaramide in the presence of Sc(OTf)₃ and methyl orthoformate furnished a diastereomeric mixture of acetals, which were readily separated by simple recrystallization. Diastereomerically pure acetal was hydrolyzed to give optically pure muscone and recovered N,N′-dibenzyl-l-tartaramide.     

Synthesis of α,β-unsaturated dioxanes, dioxolanes and dioxepanes by trans-acetalisation of dimethylacetals with meso or C2-symmetrical 1,2-, 1,3- and 1,4-diols

Several o-dibenzylic diols were prepared reacting organometallics with o-phthalaldehyde at room temperature in ether. The identity of the meso and C₂-symmetrical (d,l) isomers as well as their ratio were determined by chiral gas chromatography. The meso and C₂ (racemic) stereoisomeric diols were easily separated by flash chromatography on silica gel. A set of 18 α,β-unsaturated acetals were then prepared reacting those, as well as commercially available 1,2, 1,3 and 1,4 diols, with the corresponding methylacetals in acidic medium. A trans-acetalisation procedure adapted to the cases of fragile allylic alcohols or unfavorable 1,6 diols-derived dioxonanes based on a Dean-Stark trapping of methanol was also employed.     

Regio- and diastereoselective SN2′ or SN2″ reactions on chiral acetals of cyclic aldehydes promoted by PhCu,BF3

The regio- and diastereoselectivity of the addition of PhCu, BF₃ reagent on chiral acetals derived from several mono or dienic aldehydes was studied. It was found that monoethylenic acetals react regio- and diastereoselectively via an overall anti S_N2′ reaction. The regioselectivity observed with the dienic acetals seems to be strongly dependent on the nature of the acetal. In all cases the S_N2″reaction was the result of an anti process.     

Synthesis of indenes by ytterbium-catalyzed carboalkoxylation/Friedel-Crafts reaction of arylidenecyclopropanes with acetals

Ytterbium-catalyzed tandem carboalkoxylation/Friedel-Crafts reaction of arylidenecyclopropanes 1 with acetals 2 afforded the corresponding indene derivatives 3 in good to high yields. For example, in the presence of 10 mol % of Yb(OTf)₃ the reaction of 1-phenylbenzylidenecyclopropane 1a with the dimethyl acetals of benzaldehyde 2a, p-tolualdehyde 2b, and p-anisaldehyde 2c gave 1,3-diphenyl-2-(2-methoxyethyl)indene 3a, 2-(2-methoxyethyl)-3-phenyl-1-(p-tolyl)indene 3b, and 1-(p-anisyl)-2-(2-methoxyethyl)-3-phenylindene 3c in 82%, 80%, and 80% yields, respectively.     

Über die Herstellung des Methyl-α-D-fructopyranosides und die Struktur der dabei gebildeten Orthoester

Concerning the preparation of methyl α-D -fructopyranoside and the structure of the orthoester by-products Koenigs-Knorr glycosidation (AgClO₄/Ag₂CO₃) of the easily accessible p-nitrobenzoylated fructosylchloride 7 yields mainly the protected glycoside 3 which was deacylated to the known title compound 1 . The orthoesters 15 and 16 were formed as by-products in this glycosidation whilst the analogous orthoesters 21 and 22 are formed as main products in the glycosidation (Ag₂CO₃) of the benzoylated fructosylchloride 12 . The structure of these orthoesters was deduced mainly from their spectroscopic data, from those of their derivatives 17 , 18 , 19 , 20 , 25 and 26 and by comparison of the latter with the model compounds 31 and 34 .     

1,3-Polyol arrays via the stereoselective rearrangement of vinyl acetals

A series of 1,3-dioxanyl vinyl acetals were readily synthesized from the corresponding dioxanone by a reduction and in situ acylation followed by Petasis olefination. Treatment of these vinyl acetals with BF₃·OEt₂ results in an O to C rearrangement to form anti-3,5-dihydroxyketones while a mixture of Me₃Al and BF₃·OEt₂ provides the corresponding syn relationship via a stereoretentive rearrangement.     

Hydroalumination of silylacetylenes: a novel and highly stereoselective synthesis of (E)-telluro(silyl)ketene acetals and their applications in Sonogashira cross-coupling reactions

The hydroalumination of silylacetylenes with DIBAL-H followed by the addition of n-butyllithium generated in situ the (Z)-β-vinylorganosilane alanates intermediates, which were trapped with butyltellurenyl bromide (C₄H₉TeBr), furnishing exclusively the (E)-1-butyltelluro-1-tri(organyl)silyl-2-organyl-1-alkenes in 45-70% yields. These telluro(silyl)ketene acetals were utilized as substrates in Sonogashira cross-coupling Pd-catalyzed reactions, furnishing the (Z)-1,4-diorganyl-2-tri(organyl)silyl-1-buten-3-ynes with total control of regio- and stereochemistry in 62-80% yield.     

A novel and efficient method for inside selective esterification of terminal vic-diols

A novel and highly efficient procedure for inside selective esterification of terminal vic-diols has been achieved in one-pot via Yb(OTf)₃-catalyzed formation and partial hydrolysis of cyclic orthoesters. This method offers several advantages including wide compatibility with acid labile functional groups, and good to high regioselectivity and yields.     

Regio- and chemoselective reductive cleavage of 4,6-O-benzylidene-type acetals of hexopyranosides using BH3·THF-TMSOTf

Benzylidene-type cyclic acetals of carbohydrates undergo efficient reductive ring opening using BH₃·THF and a catalytic amount of TMSOTf at room temperature. 4,6-O-Benzylidene-hexopyranosides afford the corresponding 4-O-benzyl ethers exclusively, in high yields. Other benzylidene-type acetals, such as naphthylmethylene and 4-methoxybenzylidene acetals are also cleaved with the same reagent. The conversions are highly regio- and stereoselective and afford benzyl-type ethers in excellent yields.     

Studies on the chemoenzymatic synthesis of 3-phenyl-GABA and 4-phenyl-pyrrolid-2-one: the influence of donor of the alkoxy group on enantioselective esterification

A new chemoenzymatic method for the synthesis of enantiomerically pure 3-phenyl-γ-aminobutyric acid 1 and 4-phenyl-pyrrolid-2-one 9 based on the enzymatic kinetic resolution of 3-phenyl-4-pentenoic acid 2 is described herein. Enzymatic resolution of the racemic substrate provided products with good enantioselectivity upon esterification. In these reactions, a new class of alkoxy group donor—orthoesters, acetals and ketals were used. The best results of the enzymatic kinetic resolution were obtained for triethyl orthoacetate in toluene solvent.     

Peroxide‐mediated crosslinking of poly(ethylene oxide)

The crosslinking of poly(ethylene oxide) (PEO) with a difunctional peroxide such as 2,5‐bis(tert‐butylperoxy)‐2,5‐dimethylhexane (Luperox 101) may proceed through at least two different pathways. Thus, the thermally formed alkoxy radicals abstract hydrogen from PEO, and the resulting PEO radicals may combine or react with the peroxide radicals to give ether or acetal crosslinks. However, these reactions also produce noncrosslinking acetals and vinyl ethers. The acetals may react further with peroxy or other radicals and yield orthoesters and ketene acetals. These and similar groups, in the presence of dilute acids, are susceptible to acid hydrolysis, leading to the disintegration of the gels. The gels, upon swelling in dilute acids, undergo a slow degradation process that is not observed for unmodified PEO. The acid hydrolysis is confirmed by a combination of size exclusion chromatography and dynamic mechanical analysis. IR analysis shows the presence of hydroxyl end groups and the presence of carboxylates rather than aldehyde groups, this is consistent with orthoesters and ketene acetal intermediates. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 3021–3026, 2002     

Trapping enols of esters and lactones with diazomethane

A series of regioisomeric ketene-O,O-dialkyl acetals were prepared from ambident β-dicarbonylfuroindoles by trapping the enol tautomers of esters and lactones with diazomethane. Definitive structural characterization was accomplished by X-ray crystal structure determination on a ketene-O,O-dimethyl acetal (R = Me).     

Mild and efficient method for the cleavage of benzylidene acetals using HClO4-SiO2 and direct conversion of acetals to acetates

HClO₄-SiO₂ has been used successfully for the deprotection of benzylidene acetals and the direct conversion of benzylidene acetals to the corresponding di-O-acetates. The reactions are very fast and yields are excellent.     

Carbon-carbon bond formation by ‘double activation’. The synthesis of piperolide and fadyenolide intermediates.

Buenolide anions do not react with orthoesters and butenolides do not react with carbocations derived from acetals and orthoesters. However double activation of the butenolide (as the carbanion) and the alkoxyalkanes (as the stabilised carbocations) leads to high yield carbon-carbon bond formation of some generality.     

Synthesis and some properties of gem-dichlorocyclopropane carboxaldehyde acetals and cyclopropane carboxaldehyde acetals

α,β-Unsaturated aldehyde acetals add :CCl₂ (obtained in accordance with Makosza procedure) to form gem-dichlorocyclopropanecarboxaldehyde acetals (1) in high yields when the ratio of reactants is no less than 1:4. The addition of :CCl₂ to polyunsaturated aldehyde acetals in the above conditions proceeds regioselectively at double bonds enriched by electrons. Compounds 1 are reduced by sodium in liquid ammonia to give cyclopropanecarboxaldehyde acetals (2). Both 1 and 2 are hydrolized by dilute H₃P0₄ to the corresponding aldehydes and are added to vinyl ethers in the presence of BF₃·Et₂O to produce only 1:1 adducts which are hydrolyzed by a mixture of AcOH-AcONa-H₂O to give β-formylcyclopropanes which were previously unknown.     

Diammonium hydrogen phosphate: a versatile and inexpensive reagent for one-pot synthesis of dihydropyrimidinones, quinazolinones and azalactones under solvent-free conditions

Diammonium hydrogen phosphate, (NH₄)₂HPO₄, efficiently catalyzes the three-component Biginelli reaction between an aldehyde, a β-dicarbonyl compound and urea or thiourea under solvent-free conditions to afford the corresponding dihydropyrimidinones in high yields. Also, the synthesis of 2,3-disubsitituted-(3H)-quinazolin-4-ones is achieved by the one-pot reaction of isatoic anhydride, primary amines and orthoesters in the presence of (NH₄)₂HPO₄. The reaction of hippuric acid with aromatic aldehydes and acetic anhydride resulted in the formation of azalactones using catalytic amounts of (NH₄)₂HPO₄.