Yb(OTf)3-catalyzed reactions of 5-alkylidene Meldrum's acids with phenols: one-pot assembly of 3,4-dihydrocoumarins, 4-chromanones, coumarins, and chromones

[reaction: see text] The Yb(OTf)3-catalyzed annulation reactions of phenols with 5-alkylidene Meldrum's acids enabled the synthesis of structurally diverse heterocycles in high isolated yields. A series of 4-substituted 3,4-dihydrocoumarins, 2,2-disubstituted 4-chromanones, coumarins, and 2-substituted chromones were readily and efficiently assembled, including the naturally occurring coumarins citropten, scoparone, and ayapin. Addition of phenols to biselectrophilic 5-alkylidene Meldrum's acids proceeded through two distinct multibond-forming modes: Friedel-Crafts C-alkylation/O-acylation and Friedel-Crafts C-acylation/O-alkylation. The regioselectivity of the catalytic annulation reaction was controlled by the degree of substitution on the alkylidene moiety.     

Asymmetric synthesis of all-carbon benzylic quaternary stereocenters via Cu-catalyzed conjugate addition of dialkylzinc reagents to 5-(1-arylalkylidene) Meldrum's acids

The asymmetric synthesis of all-carbon benzylic quaternary stereocenters has been successfully achieved through copper-catalyzed addition of dialkylzinc reagents to 5-(1-arylalkylidene) and 5-(dihydroindenylidene) Meldrum's acids in the presence of phosphoramidite ligand. The resulting benzyl-substituted Meldrum's acids and 1,1-disubstituted indanes were obtained in good yields and up to 99% ee. The significance of substituting the position para, meta, and ortho to the electrophilic benzylic center was highlighted. A benzyl Meldrum's acid product was further transformed to a 3,3-disubstituted 1-indanone and a beta,beta-disubstituted pentanoic acid.     

Stereoselective synthesis of 3-alkylidene/alkylazetidin-2-ones from azetidin-2,3-diones

Azetidin-2,3-diones have been used as synthons for the synthesis of C-3 alkylidene/alkylazetidin-2-ones. Some of the 3-alkylazetidin-2-ones are well known for their cholesterol absorption inhibitor activity. A regio and stereoselective Grignard reaction on a keto group followed by dehydration using PPh₃/CCl₄ reagent is a key step in this synthesis. Hydrogenation of the 3-alkylideneazetidin-2-ones provided stereoselectively cis-3-alkylazetidin-2-ones in very good yields.     

A facile protocol for the preparation of 5-alkylidene and 5-imino substituted hydantoins from N,N′-disubstituted parabanic acids

A convenient procedure for the preparation of various substituted (thio)hydantoins is described. The method is based on Wittig and aza-Wittig reactions of parabanic acids with phosphonium ylides. The reactions occurred both regio- and stereo-selectively.     

Tandem catalysis for the synthesis of 2-alkylidene cyclohexenones

(5R,6S,E)-5-Alkyl-2-(2-(methoxymethoxy)ethylidene)-6-(phenylsulfonyl)cyclohex-3-enones, have been obtained by a domino reaction using tandem catalysis with a Nazarov reagent 3, and several unsaturated aldehydes.     

Ultrafast multisequential photochemistry of 5-diazo Meldrum's acid

We disclose the light-induced dynamics and ultrafast formation of several photoproducts from the manifold of reaction pathways in the photochemistry of 5-diazo Meldrum's acid (DMA), a photoactive compound used in lithography, by femtosecond mid-infrared transient absorption spectroscopy covering several nanoseconds. After excitation of DMA dissolved in methanol to the second excited state S(2), 70% of excited molecules relax back to the S(0) ground state. In competing processes, they can undergo an intramolecular Wolff rearrangement to form ketene, which reacts with a solvent molecule to an enol intermediate and further to carboxylate ester, or they first relax to the DMA S(1) state, from where they can isomerize to a diazirine and via an intersystem crossing to a triplet carbene. For a reliable identification of the involved compounds, density functional theory calculations on the normal modes and Fourier transform infrared spectroscopy of the reactant and the photoproducts in the chemical equilibrium accompany the analysis of the transient spectra. Additional experiments in ethanol and 2-propanol lead to slight spectral shifts as well as elongated time constants due to steric hindrance in transient spectra connected with the ester formation channel, further substantiating the assignment of the occurring reaction pathways and photoproducts.     

Modular synthesis of di- and tripeptides of luminescent crown ether aminocarboxylic acids

Luminescent benzo crown ether aminocarboxylic acids with ammonium ion affinity were prepared and converted into linear bis- and tris benzo crown ether amides using standard peptide coupling protocols. The affinities of the new crown ethers to ammonium ions and di- and tetrapeptides bearing ammonium ion moieties were determined by emission titration in methanol and buffered water.     

A novel route to 5-substituted 3-isoxazolols. Cyclization of N, O-DiBoc beta-keto hydroxamic acids synthesized via acyl Meldrum's acids

3-Isoxazolols are most often synthesized from a beta-keto ester and hydroxylamine. This cyclization typically gives rise to a major byproduct, the corresponding 5-isoxazolone. We have found that N, O-diBoc-protected beta-keto hydroxamic acids can be synthesized and cyclized to 5-substituted 3-isoxazolols without formation of any byproduct. We present a novel and versatile three-step procedure in which carboxylic acid derivatives are converted into acyl Meldrum's acids which, upon aminolysis with N, O-bis(tert-butoxycarbonyl)hydroxylamine, lead to the N, O-diBoc-protected beta-keto hydroxamic acids. These hydroxamic acid analogues were then, upon treatment with hydrochloric acid, cyclized to the corresponding 5-substituted 3-isoxazolols.     

Synthesis of Triketones from Meldrum's Acid

Russian Journal of Organic Chemistry -     

Electrophilicity parameters of 5-benzylidene-2,2-dimethyl[1,3]dioxane-4,6-diones (benzylidene Meldrum's acids)

Kinetics of the reactions of four benzylidene Meldrum's acids 1 with acceptor-substituted carbanions 2 were studied photometrically in DMSO at 20 degrees C. The reactions follow second-order kinetics, and the second-order rate constants were found to follow the correlation log k2 (20 degrees C) = s(N + E) (eq 1), which was used to calculate the electrophilicity parameters E for compounds 1. Hammett correlations are given, which allow one to assign electrophilicity parameters for various beta,beta-acceptor substituted styrenes and thus to predict a large number of absolute rate constants for a manifold of Michael additions. The reactions of primary and secondary amines are approximately 2 orders of magnitude faster than predicted by the correlation (1), supporting transition states which are stabilized by hydrogen bridges from NH to the carbonyl groups of the benzylidene Meldrum's acids.     

A stereoselective synthesis of the allo-bile acids from the 5β-isomers

The allo-bile acids are a subset of the family of steroidal detergents found in most vertebrates. Because there are no major biological feedstocks for isolation of the allo-bile acids, they must be synthesized from the abundant 5β-reduced isomers. Here we report a general set of methods for the synthesis of allo-bile acids from the corresponding 5-β isomers demarcated by a selective C-3 oxidation, IBX unsaturation, and stereoselective saturation.     

Modular synthesis of 5-substituted thiophen-2-yl C-2'-deoxyribonucleosides

A new modular methodology of preparation of 5-substituted thiophene-2-yl C-nucleosides was developed. A Friedel-Crafts-type of C-glycosidation of 2-bromothiophene with toluoyl-protected methylglycoside 2 gave the desired protected 1beta-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose 4a in 60%. The key intermediate 4a was then subjected to a series of palladium-catalyzed cross-coupling reactions. The cross-coupling reactions with alkyl organometallics gave beta-(5-alkylthiophen-2-yl)-2-deoxyribonucleosides 4 and 7 in moderate yields accompanied by side-products of reduction. On the other hand, cross-couplings with arylstannanes proceeded smoothly to give a series of beta-(5-arylthiophen-2-yl)-2-deoxyribonucleosides 4 in good yields. Deprotection of toluoylated nucleosides by NaOMe in MeOH and silylated nucleosides by Et 3N.3HF gave a series of free C-nucleosides 6. Alternatively, other types of 5-arylthiophene C-nucleosides 6 were prepared in one step by the aqueous-phase cross-coupling reactions of unprotected 1beta-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose with boronic acids. Title 5-arylthiophene C-nucleosides 6 exhibit interesting fluorescent properties with emission maxima varying from 339 to 396 nm depending on the aryl group attached.     

Meldrum's acids as acylating agents in the catalytic intramolecular Friedel-Crafts reaction

[reaction: see text] The intramolecular Friedel-Crafts acylation of aromatics with Meldrum's acid derivatives catalyzed by metal trifluoromethanesulfonates is reported. Meldrum's acids are easily prepared, functionalized, handled, and purified. The synthesis of polysubstituted 1-indanones from benzyl Meldrum's acids was investigated thoroughly, and it was shown that a variety of catalysts were effective, while accommodating a diversity of functional groups under mild conditions. The scope, limitations, and functional group tolerance (terminal alkene and alkyne, ketal, dialkyl ether, dialkyl thioether, aryl methyl ether, aryl TIPS and TBDPS ethers, nitrile- and nitro-substituted aryls, alkyl and aryl halides) for a variety of 5-benzyl (enolizable Meldrum's acids) and 5-benzyl-5-substituted Meldrum's acids (quaternized Meldrum's acids), forming 1-indanones and 2-substituted-1-indanones, respectively, are delineated. This method was further applied to the synthesis of 1-tetralones, 1-benzosuberones, and the potent acetylcholinesterase inhibitor donepezil. Rate of cyclization as a function of ring size was established for various benzocyclic ketones via competition experiments: 1-tetralones form faster than both 1-indanones and 1-benzosuberones, and 1-benzosuberones cyclize faster than 1-indanones.     

Preparation and improved stability of N-Boc-alpha-amino-5-acyl Meldrum's acids,a versatile class of building blocks for combinatorial chemistry

The preparation of novel N-Boc-alpha-amino-5-acyl Meldrum's acids is described. The synthetic inaccessibility and instability of several of these products have led to the development of a protocol that allows the synthesis of their corresponding 4-(dimethylamino)pyridine (DMAP) salts (5-AMA-DMAP's), which exhibit superior stability compared to that of the free 5-AMA. A simple and expedient ion-exchange method was developed for the quantitative removal of DMAP to liberate the synthetically useful DMAP-free form when needed.     

A convenient synthesis of coumarin-3-carboxylic acids via Knoevenagel condensation of Meldrum's acid with ortho-hydroxyaryl aldehydes or ketones

Coumarin-3-carboxylic acids were obtained in high yields with excellent purity from ortho-hydroxybenzaldehydes and Meldrum's acid after a 2 h reflux in ethanol. The less reactive ketones were first reacted with alcoholic ammonia to form ketimines, which were then condensed with Meldrum's acid to generate 4-alkylcoumarin-3-carboxylic acids in moderate yields.     

Modular synthesis of fluorous trialkylphosphines

A modular synthetic protocol was developed for the preparation of fluorous trialkylphosphines with a different number of methylene spacers and various lengths of the fluorous ponytails P[(CH(2))(A)R(FX)][(CH(2))(B)R(FY)][(CH(2))(C)R(FZ)] (A, B, C = 3 and 4; X, Y, Z = 4, 6, and 8). [reaction: see text]     

Modular synthesis of heparin oligosaccharides

A general, modular strategy for the first completely stereoselective synthesis of defined heparin oligosaccharides is described. Six monosaccharide building blocks (four differentially protected glucosamines, one glucuronic and one iduronic acid) were utilized to prepare di- and trisaccharide modules in a fully selective fashion. Installation of the alpha-glucosamine linkage was controlled by placing a conformational constraint on the uronic acid glycosyl acceptors thereby establishing a new concept for stereochemical control. Combination of disaccharide modules to form trans-uronic acid linkages was completely selective by virtue of C2 participating groups. Coupling reactions between disaccharide modules exhibited sequence dependence. While the union of many glucosamine uronic acid disaccharide modules did not meet any problems, certain sequences proved not accessible. Elaboration of glucosamine uronic acid disaccharide building blocks to trisaccharide modules by addition of either one additional glucosamine or uronic acid allowed for stereoselective access to oligosaccharides as demonstrated on the example of a hexasaccharide resembling the ATIII-binding sequence. Final deprotection and sulfation yielded the fully synthetic heparin oligosaccharides.