Application of 3,3′-disubstituted xylBINAP derivatives in inter- and intramolecular asymmetric Heck/Mizoroki reactions

3,3′-Disubstituted xylBINAP derivatives were applied to inter- and intramolecular asymmetric Heck/Mizoroki reactions. The results from these reactions were compared to those obtained with (R)-xylBINAP, (S)-BINAP and 3,3′-disubstituted BINAP derivatives. Catalysts derived from 3,3′-disubstituted xylBINAP ligands were found to be most effective in the arylation of 2,3-dihydrofuran in terms of reaction times, conversions, and product enantioselectivity.     

Stereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates

Diastereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates is described. Regioselective ring-opening reactions of 1,2-cyclic sulfamidates derived from L-phenylalanine, alanine, valine, norvaline with the ketal protected acetylide with a phenyl substituent proceed smoothly to form the N-sulfamate intermediates which on acidic hydrolysis give alkynylated amines with the ketal group intact. Hydrogenation of the alkynylated amines, debenzylation, ketal deprotection, subsequent cyclization (of aminoketones) and stereoselective hydrogenation of the cyclic iminium ion intermediates afford the corresponding cis-2,6-disubstituted piperidines in high diastereoselectivity (98%?≥?d.e.) with good chemical yields (68–86%). The present approach provides a novel route for the stereoselective synthesis of cis-2,6-disubstituted piperidines.     

Click chemistry methodology in the synthesis of anabasine and cytisine conjugates with isoxazole derivatives

Cytisine and anabasine derivatives containing an acetylenic fragment were used as building blocks in 1,3-dipolar cycloaddition reactions with substituted N-hydroxybenzenecarboximidoyl chlorides, catalyzed by copper(I) salt. The reactions with N-propargylcytisine were not selective, and the products were mixtures of 3,5-disubstituted isoxazoles and small amounts (5–8%) of 3,4-disubstituted isomers. 1,3-Dipolar cycloaddition with N-propargylanabasine afforded 3,5-disubstituted isoxazole derivatives with high regioselectivity.     

A highly stereoselective transformation of carboxylic esters to trisubstituted olefins via cationic cyclopropyl-allyl rearrangement of sulfonates of cis-1,2-disubstituted cyclopropanols

Methanesulfonates of readily available cis-1,2-disubstituted cyclopropanols on reaction with magnesium bromide in diethyl ether undergo cyclopropyl-allyl rearrangement to afford allyl bromides, with an (E)-trisubstituted double bond, as main products. The amount of the corresponding (Z)-isomers did not exceed 5% when the reaction was performed at 0 °C, and the major concomitant products were the regioisomeric secondary bromides. The latter are sufficiently less reactive towards sulfur, phosphorus and hydrogen nucleophiles than the dominant (E)-disubstituted allyl bromides and these reactions are suitable for the stereoselective preparation of trisubstituted olefins.     

Tetraphosphine/palladium-catalyzed Heck reactions of aryl halides with disubstituted alkenes

cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C₃H₅)]₂ efficiently catalyses the Heck reaction of disubstituted alkenes such as methyl crotonate, ethyl cinnamate, methyl methacrylate or α-methylstyrene with a variety of aryl halides. In the presence of 1,2-disubstituted alkenes the stereoselectivities of the reactions strongly depend on the substituents of the alkenes. Selectivities up to 97% in favor of E-isomers can be obtained for the addition to methyl crotonate. With the 1,1-disubstituted alkenes methyl methacrylate or α-methylstyrene mixtures of products are obtained.     

Application of an Ugi type reaction to an N-silyl-4,4-disubstituted 1,4-dihydropyridine

Ugi type reactions of an N-silyl-4,4-disubstituted 1,4-dihydropyridine with various isocyanides and carboxylic acids provided 2-carbamoylated 1,2,3,4-tetrahydropyridine derivatives in good yields and with high stereoselectivities.     

Regioselective hydrostannation of highly hindered arylalkynes under ortho-directing effects

Palladium-catalyzed hydrostannation reactions of ortho-disubstituted arylalkynes were achieved with total stereo- and regio-selectivity in THF at room temperature. The regioselectivity was found to be under the control of the ortho-substituents (ortho-directing effects, ODE) and pure α-vinylstannanes are produced in good yields and as single isomers regardless of the substituents’ nature. These hydrostannation α-products are precursors of choice for the preparation of stereo-defined triarylolefins.     

Direct transformation of N,N-disubstituted amides and isopropyl esters to nitriles

Various N,N-dimethyl amides, N-methoxy-N-methyl amides, and isopropyl esters were smoothly transformed into the corresponding nitriles in good to moderate yields by the treatment with diisobutylaluminium hydride, followed by treatment with molecular iodine in aq ammonia. The present reactions are novel one-pot and practical methods for the transformation of N,N-disubstituted amides and isopropyl esters into nitriles, through the formation of hemiaminal O-AlBu₂ and hemiacetal O-AlBu₂, respectively.     

Study on the cyclization of 6-arylethynylpyrimidine-5-carbaldehydes with tert-butylamine: microwave versus thermal preparation of pyrido[4,3-d]pyrimidines

Thermal and microwave initiated cyclization of 2,4-disubstituted 6-arylethynylpyrimidine-5-carbaldehydes with tert-butylamine has been studied. A novel high-yielding preparation of 2,4-disubstituted 7-arylpyrido[4,3-d]pyrimidines has been developed. The intermediate compounds were isolated and possible mechanism of the reactions is discussed.     

Cross-coupling reaction on N-(3,5-dibromo-2-pyridyl)piperazines: regioselective synthesis of 3,5-disubstituted pyridylpiperazines

Unsymmetrical 3,5-disubstituted pyridylpiperazines were prepared from tribromopyridine in three coupling reactions. Key to the success of the syntheses is the palladium-catalyzed regioselective cross-coupling reaction in the 3-position of N-(3,5-dibromo-2-pyridyl)piperazines.     

Microwave-assisted, Ir-catalyzed aromatic C–H borylation

One-step conversions of 1,3-disubstituted benzenes to aryl boronates and 2,6-disubstituted pyridines to heteroaryl boronates are described. Microwave heating was used for all reactions. [(COD)Ir(μ-OMe)]₂ and 4,4′-di-tert-butyl-2,2′-bipyridine were used as catalysts, in methyl tert-butyl ether. Acceleration of the rate of reaction was remarkable compared with that of same reaction under conventional heating conditions.     

Highly cis- and trans-selective alkyl radical addition to α-methylene-γ-phenyl-γ-butyrolactams

The 1,3-asymmetric induction in alkyl radical additions to α-methylene-γ-phenyl-γ-butyrolactams was investigated. The reactions of N-unsubstituted lactam using (Me₃Si)₃SiH under UV irradiation give cis-α,γ-disubstituted lactams, whereas reactions of N-pivaloyllactams using Et₃B and Bu₃SnH in the presence of Yb(OTf)₃ give trans-α,γ-disubstituted lactams, both with high diastereoselectivities.     

PtCl2-catalyzed reactions of o-alkynylanilines with ethyl propiolate and dimethyl acetylenedicarboxylate

The PtCl₂-catalyzed reactions between indoles and ethyl propiolate gave rise to mono and double addition products. The composition of the products was largely influenced by the substituents on the indoles as well as the amount of ethyl propiolate used. o-Alkynylanilines reacted with ethyl propiolate and dimethyl acetylenedicarboxylate under the catalysis of PtCl₂ to generate the corresponding 2,3-disubstituted indoles. The reaction proceeded by following a sequential cyclization/intermolecular addition pathway.     

SmI2-promoted intra- and intermolecular C-C bond formation with chiral N-acyl oxazolidinones

The suitability of chiral oxazolidinones in the SmI₂-mediated C-C bond generation between the imide functionality of an N-acyl oxazolidinone unit and an olefinic radical acceptor, in both inter- and intramolecular reactions, was investigated. It was shown that the products from an Evans asymmetric alkylation can undergo direct carbon-carbon bond formation with an acrylamide providing chiral acyclic ketones in reasonable yields. These examples represent the first transformation of such N-acyl oxazolidinones where this chiral auxiliary is removed under the conditions for ketone formation. 5-exo-trig Cyclization studies were also undertaken with the same type of substrates, providing trans-2,5-disubstituted cyclopentanones in yields of approx. 50%. However, attempts to cyclize heteroatom-containing equivalents were less rewarding.     

Synthesis of enantiopure N-protected 4,5-disubstituted 3-pyrrolidinones and N-protected 2,5-disubstituted 3-pyrrolidinones via the Dieckmann reaction of dicarbonyl compounds derived from enantiopure β-amino esters

Under the action of KHMDS in THF solvent the Dieckmann reaction of dicarbonyl compounds derived from enantiopure β-amino esters provides enantiopure N-protected 4,5-disubstituted 3-pyrrolidinones, whereas N-protected 2,5-disubstituted 3-pyrrolidinones formed in reactions mediated by tert-BuOK in DMF or toluene. Reduction of these pyrrolidinones afforded enantiopure polysubstituted pyrrolidines.     

Novel approach towards 3,7-disubstituted 1,6-naphthyridin-4(1H)-ones exploiting cross-coupling and SNAr reactions of a dihalogenated compound

A new route towards the synthesis of a series of 3,7-disubstituted 1,6-naphthyridin-4(1H)-ones in moderate to good yields is reported. The strategy involves the preparation of a 3,7-dihalogenated compound that undergoes differential functionalization using palladium-catalyzed cross-coupling and S_NAr reactions.     

Synthesis of BINOL derived phosphorodithioic acids as new chiral Brønsted acids and an improved synthesis of 3,3′-disubstituted H8-BINOL derivatives

Original phosphorodithioic acid diesters were prepared according to an improved synthesis of 3,3′-disubstituted H₈-BINOL derivatives. In preliminary experiments, these new Brønsted acids were tested as organocatalysts in three reactions. They promoted the Nazarov cyclisation with mixed selectivities, the Mannich reaction with good enantioselectivity and they catalyzed efficiently the alkylation of N-acyliminium with enol silyl ether.     

Directed ortho-metalation versus reductive amination in the preparation of polytopic,highly substituted,and sterically congested amine-S-arylthiocarbamates as thiophenol precursors

The synthesis of polydentate amine-S-arythiocarbamates was tested by directed ortho-lithiation of 2,4-disubstituted thiophenols, or the corresponding O- and S-arylthiocarbamates by deprotonation or lithium–bromine exchange, followed by addition of the electrophiles N(CH₂CH₂X)₃ (X=Br, I). In the case of the thiophenol, deprotonation resulted in a trithioether-amine upon addition of the electrophile. With the O- and S-thiocarbamates, the reactions resulted in the migration of the thiocarbamoyl group to the ortho-position (Fries rearrangement), or nucleophilic attack of the carbonyl group by butyllithium, respectively. An alternative route employed 2,4-disubstituted phenols to obtain the corresponding salicylaldehydes, and subsequently the O-arylthiocarbamates for Newman–Kwart thermal rearrangement (NKR). Finally, the formyl group on the S-arylthiocarbamates allowed reductive amination to assemble polytopic compounds with amine and S-thiocarbamate groups.     

Dibutylphosphate (DBP) mediated synthesis of cyclic N,N′-disubstituted urea derivatives from amino esters: a comparative study

The N,N′-disubstituted urea derivatives such as amino acid hydantoins and dihydrouracil derivatives were prepared starting from natural and unnatural amino acid esters using dibutylphosphate (DBP). During the attempted synthesis of N-heterocycles with larger than six-membered rings containing the N,N′-disubstituted urea functionalities, three unexpected products namely squamolone, N-methyl pyrrolidine-2-one, and diketopiperazine were isolated.     

New domino approach for the synthesis of 2,3-disubstituted benzo[b]furans via copper-catalyzed multi-component coupling reactions followed by cyclization

An efficient domino process for the construction of 2,3-disubstituted benzo[b]furans has been developed via copper-catalyzed three-component coupling reactions of salicylaldehydes, amines, and alkynes followed by base-assisted O-annulation reaction.