Reactions of dimedone-β-benzoylacrylic acid adduct with nitrogen-containing binucleophiles

2-(2-Hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-4-oxo-4-phenylbutanoic acid (dimedone adduct with β-benzoylacrylic acid) reacted with ethylenediamine and benzidine to give bis-quinoline derivatives. In the reaction with tryptamine a product containing hexahydroquinoline and indole fragments was obtained, while the reaction with phenylhydrazine hydrochloride afforded pyridazine derivative. The reactions with o- and p-phenylenediamines involved retro-Michael decomposition of the initial adduct and formation of enamino derivatives of dimedone.     

An efficient synthesis of α-aryl β-(N-tosyl)amino phosphonate derivatives from α-diazophosphonate

The α-diazophosphonate was added to aryl (N-tosyl)imine to give β-aryl β-(N-tosyl)amino α-diazophosphonates, which were further subjected to TsOH-catalyzed diazo decomposition to yield α-aryl β-(N-tosyl)enaminophosphonates through 1,2 aryl migration. The α-aryl β-(N-tosyl)enamino phosphonates were hydrogenated to give α-aryl β-(N-tosyl)amino phosphonates.     

Heck reactions of aryl bromides with alk-1-en-3-ol derivatives catalysed by a tetraphosphine/palladium complex

cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C₃H₅)]₂ efficiently catalyses the Heck reaction of alk-1-en-3-ol with a variety of aryl bromides. In the presence of hex-1-en-3-ol or oct-1-en-3-ol, the β-arylated carbonyl compounds were selectively obtained. Linalool and 2-methylbut-3-en-2-ol led to the corresponding 1-arylalk-1-en-3-ol derivatives. Turnover numbers up to 69,000 can be obtained for this reaction. A minor electronic effect of the substituents of the aryl bromide was observed. Similar reaction rates were observed in the presence of activated aryl bromides such as bromoacetophenone and deactivated aryl bromides such as bromoanisole.     

Triazolyl C-nucleosides via the intermediacy of β-1′-ethynyl-2′-deoxyribose derived from a Nicholas reaction: Synthesis,photophysical properties and interaction with BSA

We report the design and synthesis of triazolyl donor/acceptor unnatural C-nucleosides via alkyne (sugar)—azide (aromatic) 1, 3-dipolar cyclo-addition reaction as a key step and studies on their photophysical properties. We have chosen β-1′-ethynyl-2′-deoxyribose as a precursor to synthesize triazolyl-C-nucleosides. Overcoming the difficulties, we obtain β-1′-ethynyl-2′-deoxyribose as a major product following a Co₂(CO)₈ catalyzed intramolecular Nicholas reaction. The 1,3-diaxial interaction is the driving force for the α to β-anomeric conversion while performing cobalt complexation followed by oxidation to afford β-1′- ethynyl-2′-deoxyribose as the major product. A Cu(I)-catalyzed click reaction between different aromatic donor/acceptor azides and β-1′- ethynyl-2′-deoxyribose generates the desired unnatural triazolyl donor-acceptor aromatic C-nucleosides (^cTB_Do/Ac) within 30 min. Single crystal X-ray structure shows the puckered conformation of sugar as C3′-exo. Studies on the photophysical properties suggests good fluorophoric as well as solvatochromic characteristics of these nucleosides. Two of the synthesised nucleosides, ^cTAnthB_Do and ^cTPyB_Do, are found to interact with BSA as the only tested protein with quenching of fluorescence signal. The designed bases, thus, might find applications in stabilizing a DNA and in the biophysical study thereof, if a pair of such donor acceptor C-nucleosides could be incorporated into a DNA sequence.     

Synthesis of β-aryl ketones by tetraphosphine/palladium catalysed Heck reactions of 2- or 3-substituted allylic alcohols with aryl bromides

Through the use of [PdCl(C₃H₅)]₂/cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as a catalyst, a range of aryl bromides undergoes Heck reaction using 2- or 3-subtituted allylic alcohols. With these sterically congested alkenes, the selective formation of β-aryl ketones was observed when appropriate reaction conditions were used. The influence of the functional group on the aryl bromide and of the base on the selectivity is remarkable. With several substrates, much higher selectivities were obtained using NaHCO₃ instead of K₂CO₃ as base. Furthermore, this catalyst can be used at low loading with several substrates.     

Cationic iridium complex is a new and efficient Lewis acid catalyst for aldol and Mannich reactions

A cationic iridium complex [Ir(cod)₂]SbF₆ was found to be a new and efficient Lewis acid catalyst for Mukaiyama aldol and Mannich reactions. Aldehydes react smoothly with silyl enol ethers to give β-siloxy ketones in the presence of 0.5 mol % of [Ir(cod)₂]SbF₆. The reaction of N-alkyl arylaldimines with ketene silyl acetals in the presence of 5 mol % [Ir(cod)₂]SbF₆/P(OPh)₃ gave β-amino esters. After Mannich reaction was complete, stirring of the reaction mixture for 24 h led to cyclization to give β-lactam. The reaction of N-aryl benzaldimine with silyl enol ether derived from acetophenone gave a tetrahydroquinoline derivative as a single diastereomer.     

Thiocarbamoylation of 1,2,3,4-tetrahydroisoquinoline enamines with phenyl isothiocyanate

Reactions of 1,3,3-trimethyl-3,4-dihydroisoquinoline and its benzo[f] derivative with phenyl isothiocyanate gave the corresponding enamino thioamides. Enamino ester, enamino amides, and enamino nitriles of the 1,2,3,4-tetrahydroisoquinoline series reacted with phenyl isothiocyanate in a similar way. The resulting enamino thioamides underwent acylation with acid chlorides at the β-carbon atom of the enamino fragment. The structure of the obtained enamino thioamides is stabilized by intramolecular H-bonding.     

Multicomponent Hantzsch cyclocondensation as a route to highly functionalized 2- and 4-dihydropyridylalanines, 2- and 4-pyridylalanines, and their N-oxides: preparation via a polymer-assisted solution-phase approach

An improved and efficient entry to highly functionalized β-(2-pyridyl)- and β-(4-pyridyl)alanines and the corresponding 1,4-dihydro and N-oxide derivatives has been developed by one-pot thermal Hantzsch-type cyclocondensation of aldehyde-ketoester-enamine systems in which one of the reagents (aldehyde or ketoester) was carrying the unmasked but protected chiral glycinyl moiety. Thus coupling N-Boc-O-benzyl aspartate β-aldehyde, acetoacetate and aminocrotonate esters afforded tetrasubstituted β-(4-dihydropyridyl)alanines (75% yield). One of these products was almost quantitatively transformed into the β-(4-pyridyl)alanine derivative which in turn was oxidized to the corresponding N-oxide. Each of these enantiomerically pure (Mosher's amide analysis) heterocyclic α-amino acids was incorporated into a tripeptide by coupling with (S)-phenylalanine. In a similar way tetrasubstituted β-(2-dihydropyridyl)alanine, β-(2-pyridyl)alanine and β-(1-oxido-2-pyridyl)alanine were prepared via Hantzsch cyclocondensation reaction using benzaldehyde, aminocrotonate, and acetoacetate carrying the N-Boc-O-benzyl glycinate moiety. It was shown that the work up of the reaction mixtures derived from the cyclocondensation and oxidation reactions can be carried out by the use of polymer supported reagents and sequestrants thus allowing the isolation of the products in high purity without any chromatography.     

Unusual reaction of β-hydroxy α-diazo carbonyl compounds with TsNHNCHCOCl/Et3N

The reaction of β-hydroxy α-diazo carbonyl compounds with TsNHNCHCOCl/Et₃N gave β-(p-tolylsulfonyl) α,β-unsaturated carbonyl compounds or β-(p-tolylsulfonyl) α-diazo esters. The reaction mechanism is discussed.     

ZrCl4-catalyzed X-C/C-C bond formation for the geometric selective synthesis of (E)-β-iodo aza Morita-Baylis-Hillman (MBH) adducts

A geometric selective synthesis of (E)-β-iodo and β-alkyl vinyl ketones (MBH amino adducts) has been developed through a three-component Mannich-type reaction. The reaction was conveniently conducted by generating 3-iodo allenolate intermediates via the α,β-unsaturated addition of TMS-I to 3-butyn-2-one followed by a carbonyl addition onto N-aryl imines in the presence of ZrCl₄ catalyst. The resulting β-iodo allylic amines can be readily converted into β-alkyl Morita-Baylis-Hillman adducts by performing Suzuki and Kumada cross-couplings.     

Reaction of 2-chloromethylphenols with enaminones

The reaction of o-(chloromethyl)phenols with enamino ketones afforded a series of 3-acyl- and 3-formyl-4H-chromenes as a result of cascade transformation including [4 + 2]-cycloaddition of enamino ketone to o-quinone methide generated in situ and subsequent elimination of secondary amine.     

Effects of stereochemistry and β-substituents on the rates of vinylic SN2 reaction of hypervalent vinyl(phenyl)-λ-iodanes with tetrabutylammonium halides

Both stereoisomers of β-(2-phenylethoxy)vinyl-λ³-iodane and (Z)-β-aroyloxyvinyl-λ³-iodane were prepared stereoselectively. These substituted vinyl-λ³-iodanes undergo nucleophilic vinylic substitutions with n-Bu₄NX (X=Cl, Br, I) under mild conditions, yielding vinyl halides. The observed inversion of configuration at the ipso vinylic carbon atom is compatible with a concerted vinylic S_N2 mechanism. Kinetic measurements indicated that the rates for vinylic S_N2 reaction of (Z)-vinyl-λ³-iodane are greater than those of the E-isomer, probably because of the higher ground state energy of the Z-isomer. Electronic effects of β-substituents of vinyl-λ³-iodanes in the vinylic S_N2 reaction are also discussed.     

Catalyst-free Mannich-type reaction of 1-(N-acylamino)alkyltriphenylphosphonium salts with silyl enolates

A catalyst-free reaction of 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates with silyl enolates was developed to prepare β-amino carbonyl compounds. The reported method is a useful approach for the preparation of N-protected β-amino esters as well as N-protected β-amino ketones. The starting 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates are readily available from N-protected α-amino acids. Therefore, the presented approach can be considered a new method for the α-homologation of N-protected α-amino acids to prepare β-amino acid derivatives.     

Novel efficient synthesis of β-fluoro-β-(trifluoromethyl)styrenes

CF₃CFBr₂ was employed in catalytic olefination reactions of aromatic aldehydes. In situ prepared hydrazones of aldehydes were transformed to β-fluoro-β-(trifluoromethyl)styrenes by reaction with CF₃CFBr₂ under CuCl catalysis. Based on this reaction, a novel stereoselective approach towards β-fluoro-β-(trifluoromethyl)styrenes was elaborated. Nucleophilic vinylic substitution of fluorine by secondary amines, thiolates and alkoxides in β-fluoro-β-(trifluoromethyl)styrenes was also tested.     

Investigation of the effects of various parameters on the synthesis of oligopeptides in aqueous solution

Oligomerization efficiency of amino acids in aqueous solution has been compared under different conditions (temperature, activating agent, etc.) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1,1^′-carbonyldiimidazole (CDI) as coupling agents. Glycine (H₂N-CH₂-COOH) and α-alanine (H₂N-CH(CH₃)-COOH) were chosen as α-amino acids and β-alanine (H₂N-CH₂-CH₂-COOH) as the β-amino acid. The coupling reaction between EDC and glycine was shown to occur but does not go to completion either at ambient temperature or at 70 °C. The presence of a carboxylic activating agent such as N-hydroxysuccinimide improves the EDC-mediated coupling reaction, and the amino acid structure (α- or β-) was shown to have an influence on the oligomerization efficiency, with β-alanine polymerisation being more efficient. These findings are explained by reference to the reaction mechanism.     

On the Mechanism and Scope of a Novel Nitroolefin Rearrangement

D-Labelling permits differentiation between three plausible mechanistic pathways in the novel transformation of vinylaziridine 1 with β-nitrostyrene 4 to nitro enamino olefin 5. The results are consistent with a retro-ene reaction proceeding under mild conditions (80°). Choice of proper substituents can guide the reaction toward formation of azepines or substituted enamines.     

Heck reactions of 2-substituted enol ethers with aryl bromides catalysed by a tetraphosphine/palladium complex

cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C₃H₅)]₂ efficiently catalyses the Heck reaction of β-substituted enol ethers with aryl bromides. Employing β-methoxystyrene, 3-ethoxyacrylonitrile or methyl 3-methoxyacrylate, the regioselective α-arylation of these enol ethers was observed in all cases, and mixtures of Z and E isomers were generally obtained, which in many cases yielded a single ketone product after acid treatment. The stereoselectivity of this reaction depends on steric and electronic factors, and better stereoselectivities in favour of Z isomers were observed with electron-rich or sterically congested aryl bromides. Better yields were obtained for this reaction with electron-rich or sterically congested aryl bromides than with electron-poor aryl bromides. This observation suggests that with these β-substituted enol ethers the rate-limiting step of the catalytic cycle is not the oxidative addition of the aryl bromide to the palladium complex.     

Tandem enantioselective conjugate addition-Mannich reactions: efficient multicomponent assembly of dialkylzincs, cyclic enones and chiral N-sulfinimines

A convenient access to enantiopure β-amino ketones through a multicomponent reaction of dialkyl zinc reagents, cyclic enones and chiral N-tert-butanesulfinimines is disclosed. Four diastereoisomers can be selectively obtained by the appropriate choice of the chiral ligand (L or ent-L) and the chiral N-sulfinimine (R_S or S_S). The protocol is particularly efficient when enolisable N-sulfinimines are used.     

Synthesis and transformations of new dihydro-β-campholenolactone derivatives

The reaction of xenon difluoride with enamino lactone 3 furnished the new α-fluoro aldehyde 7, whereas reaction of 3 with anhydrous HF led to racemic dihydro-β-campholenolactone 6. Acid-catalysed rearrangement of α-ethylidenelactone 4 proceeded with retention of configuration to give β-campholenolactone 8. Nitrosation of the novel bicyclic enamino lactone 6 afforded the corresponding oxime 9, while acid-catalysed treatment with primary amines, 2-methyl-1H-indole, potassium cyanide and hydrazine hydrochloride, furnished the dimethylamine substitution products 11–13 and the ‘ring switched’ product 14. The structures were determined by 2D NMR techniques, NOESY spectroscopy and X-ray diffraction.     

Recyclable C2-symmetric tertiary amine-squaramide organocatalysts: Design and application to asymmetric synthesis of γ-nitrocarbonyl compounds

Simple C₂-symmetric chiral tertiary amines bearing squaramide fragments along with the 1,2-di(pyridin-2-yl)ethane spacer group have been synthesized. Among them, amine 8b with a different configuration of stereocenters in 1,2-di(pyridin-2-yl)ethane and 1,2-diaminocyclohexane units efficiently catalyzed asymmetric additions of β-dicarbonyl compounds to nitroolefins and domino reaction of ortho-(tosylamino)chalcone with β-nitrostyrene in wet (20 equiv. of H₂O) DCM, affording corresponding adducts in up to 99% yield and 94% ee. The developed procedure is scalable. Due to poor solubility in organic solvents and water, the catalyst could be readily separated from the reaction mixture and over 10 times reused in the reaction without compromising enantiomeric enrichment and yield of product.