Silver (I)-promoted asymmetric halohydrin reaction of chiral N-enoyl-2-oxazolidinones: scope and limitations

The halohydrin reaction of chiral N-enoyl-2-oxazolidinones 1 by halogen (Br₂/I₂) and water were efficiently carried out in aqueous organic solvent promoted by silver(I) with high anti- and regioselectivity and moderate to good diastereoselectivities. The alkenoyl, cinnamoyl and electron-deficient cinnamoyl substrates smoothly underwent bromohydrin reaction in aqueous acetone but no iodohydrin reaction, where as electron-rich cinnamoyl substrates preferred to undergo iodohydrin reaction in aqueous acetone with moderate diastereoselectivity and enhanced diastereoselectivity was observed in aqueous THF.     

Steric buttressing in the Pauson-Khand reactions of aryl enynes

A variety of aryl enynes have been constructed from o-iodophenol derivatives containing ortho-tert-butyl groups via O-alkylation and a Sonogashira cross-coupling reaction. These substrates undergo efficient thermal and oxidative intramolecular Pauson-Khand reactions leading to the formation of sterically congested cyclopentenones, as well as the formation of medium-sized rings, although in the latter case with unusual regioselectivity. Incorporation of a TMS moiety on the alkyne group in a higher homolog led to cyclization via the normal mode, albeit in relatively low yield.     

Selective cis-addition of C-H bonds of pyrroles and thiophenes to alkynes catalyzed by a dinuclear palladium complex

Pyrroles and thiophenes reacted with alkynes in the presence of dinuclear palladium complexes with high stereoselectivity (cis-addition) in almost all cases. While regioselectivity in the reaction with pyrroles depended on substituents on the nitrogen atom and alkynes, all reactions of thiophenes afforded 2-alkenylthiophenes.     

New features of the steady-state rate related with the initial concentration of substrate in the diphenolase and monophenolase activities of tyrosinase

Tyrosinase has two types of enzymatic activities: the hydroxylation of monophenols to o-diphenols (monophenolase activity) and oxidation of o-diphenols to o-quinones (diphenolase activity). The action on o-diphenols involves two substrates: oxygen and o-diphenol, while the mechanism proposed is a Uni Uni Bi Bi ping-pong. In this contribution, we demonstrate experimentally that there is a kinetically preferred pathway, which translates into the appearance of curves of initial velocity vs. initial diphenol concentration shows inhibition by an excess of substrate, while sigmoid curves are obtained when the initial velocity vs. initial oxygen concentration are graphed. However, the action mechanism of the enzyme on monophenols, which is more complex because it involves three substrates (monophenol, oxygen and o-diphenol), does behave differently from the hyperbolic behaviour as regards the initial velocity vs. initial monophenol concentration, results that can be explained if the limiting step in the action of tyrosinase is the hydroxylation of monophenol to o-diphenol.     

Regioselective access to substituted oxindoles via rhodium-catalyzed carbene C-H insertion

Rhodium-catalyzed decomposition of diazoamides followed by insertion of the resulting carbenes into an aromatic C-H bond gives access to substituted oxindoles. The reaction takes place with aromatic rings substituted by either electron-donating or -withdrawing groups at ortho, meta or para positions and the regioselectivity can be controlled by a substitution α to the diazo functionality. In the presence of an ester, the reaction leads to the formation of 2-silyloxyindole-3-carboxylates in 40-85% yields and regioselectivities up to 80% are observed in the case of meta-substituted substrates. This selectivity mainly relies on steric factors and use of a more bulky N,N-diethylamide then affords 2-silyloxyindole-3-carboxamides in 42-91% yields with complete regioselectivity.     

Transformations of 5-chloro-2-hydrazino-4-<Emphasis Type="Italic">p</Emphasis>-tolylsulfonyl-1,3-thiazole

Accessible 2,2-dichloro-1-p-tolylsulfonylethenyl isothiocyanate reacted with hydrazine hydrate to give 5-chloro-2-hydrazino-4-p-tolylsulfonyl-1,3-thiazole whose reactions with thiols and amines followed a complicated pattern. Treatment of 5-chloro-2-hydrazino-4-p-tolylsulfonyl-1,3-thiazole with acetylacetone led to the formation of previously unknown 5-chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-p-tolylsulfonyl-1,3-thiazole which reacted with O-, S-, and N-centered nucleophiles at the C⁵ atom with high regioselectivity.     

Intramolecular Pyridinium Oxide Cycloadditions: Systematic Study of Substitution,Diastereoselectivity, and Regioselectivity

Intramolecular pyridinium oxide cycloadditions form complex polycyclic nitrogenous architectures. The diastereoselectivity and regioselectivity of pyridinium oxide cycloadditions was systematically investigated for the first time using complex substrates. Predictably high levels of diastereoselectivity and regioselectivity are observed, which can be attributed to minimization of steric (syn-pentane) and torsional strain in the products. The reaction is reversible under the reaction conditions, and it is stereospecific with respect to the dipolarophile geometry.     

Regioselectivity of the reaction of 4H-1,2,4-triazole-3-thiol derivatives with chloroethynylphosphonates and structure of the products

Chloroethynylphosphonates reacted with 4H-1,2,4-triazole-3-thiols in anhydrous acetonitrile to afford fused heterocyclic compounds, 6-(dialkoxyphosphoryl)-3H-thiazolo[3,2-b][1,2,4]triazol-7-ium chlorides, with high regioselectivity. The products were converted into inner salts (zwitterions) of the corresponding phosphonic acids or their monoesters with the positive charge localized on N⁷. A probable reaction mechanism implies initial formation of sulfonium ion via attack by the thionic sulfur atom on the acetylenic carbon atom linked to chlorine, followed by intramolecular cyclization involving attack on the other acetylenic carbon atom by N² of the triazole ring.     

Substituent effects on rates of rhodium-catalyzed allene cyclopropanation

Rates of cyclopropanation for mono- and disubstituted allenes have been measured relative to standard substrates in reaction with aryldiazoacetate esters catalyzed by Rh₂(S-DOSP)₄. Phenylallene derivatives exhibited a linear correlation of rate with σ⁺ coefficients, indicating a resonance-based effect, though the magnitude of the effect for allenes is less than that reported for other cyclopropanations. Relative reaction rates for aliphatic allenes were found to be similar to those for aryl-substituted allenes, but silicon substitution was found to give a 5- to 14-fold rate increase. The rate enhancement effect for 1-silyl allenes can partially make up for loss of rate and regioselectivity, with 1-trimethylsilyl-1,2-butadiene exhibiting high levels of enantioselectivity and diastereoselectivity in reaction with the chiral catalyst.     

Palladium-catalyzed regiocontrolled internal heteroarylation of electron-rich olefins with heteroaryl halides

A highly efficient palladium-catalyzed Heck coupling reaction of heteroaryl halides with electron-rich vinyl ether and hydroxyalkyl vinyl ethers is described. It was found that the choice of solvent, ligand, and reaction temperature had a fundamental influence on the regioselectivity and reactivity of the reaction, and the combination of Pd(OAc)₂ and DPPF in ethylene glycol led to the most effective catalytic system. Under these conditions, a variety of heteroaryl halides reacted very quickly with electron-rich olefins to afford exclusively the branched products in good to excellent yields without employing triflates, halide scavengers, or ionic liquids.     

KMnO4-mediated direct C2-selective C−H arylation of quinoline N-oxides with aromatic hydrazines

An efficient protocol for the synthesis of 2-arylquinoline N-oxides has been developed via KMnO₄-mediated cross-coupling reaction of quinoline N-oxides with aromatic hydrazines in moderated to good yields. The reactions proceeded efficiently over a broad range of substrates with excellent regioselectivity and functional group tolerance.     

A facile stereoselective synthesis of 2-perfluoroalkyl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles

Methyl 2-perfluoroalkynoates 2 reacted readily with cyclic nitrones 1 via 1,3-dipolar cycloaddition at room temperature to give 2-perfluoroalkyl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles 3 in good to excellent yields with high diastereoselectivity and regioselectivity.     

The chemistry and structure of the P(O)NC(O) system. Part 3. Preparation of O,O-diethyl-N-acylphosphoramidates and their reactions with electrophiles

Six O, O-diethyl-N-acylphosphoramidates ( 1a-f ) were synthesized. The reactions of their conjugate bases with haloalkanes were studied. The N/(phosphoryl)O/(carbonyl)O regioselectivity varied greatly, depending on the substrate, the haloalkane, the base, and other reaction conditions. The earlier [17] reaction of N-formyl substrate 1a that led to the N-phosphorylated formamidine was extended to other substrates 1 . Again, the yields and the selectivity depended strongly on the structure of a substrate.     

RhIII-Catalyzed C−H Activation of Aryl Hydroxamates for the Synthesis of Isoindolinones

Rh^III-catalyzed C−H functionalization reaction yielding isoindolinones from aryl hydroxamates and ortho-substituted styrenes is reported. The reaction proceeds smoothly under mild conditions at room temperature, and tolerates a range of functional groups. Experimental and computational investigations support that the high regioselectivity observed for these substrates results from the presence of an ortho-substituent embedded in the styrene. The resulting isoindolinones are valuable building blocks for the synthesis of bioactive compounds. They provide easy access to the natural-product-like compounds, isoindolobenzazepines, in a one-pot two-step reaction. Selected isoindolinones inhibited Hedgehog (Hh)-dependent differentiation of multipotent murine mesenchymal progenitor stem cells into osteoblasts.     

Synthesis of hydantoins and dihydrouracils via thermally-promoted cyclization of ureidoacetamides

The synthesis of hydantoins and dihydrouracils from ureidoacetamides has been carried out at high temperature in glycol solvents. A series of substrates were prepared and examined to determine the effect of substrate structure, N-acyl substitution (X), and solvent on the course of the reaction. A dramatic effect was observed when using ureidoacetamides (e.g., X=N-methyl-N-phenyl), which led to higher yields, faster reaction times, and lower racemization of chiral substrates. The rate of racemization of a chiral hydantoin in the presence of dibenzylamine and N-methyl aniline has also been determined. The thermal cyclization methodology has been applied to the preparation of a complex hydantoin.     

HSAB-driven regioselectivity difference in the Lewis-acid catalyzed reactions of 2-C-substituted glycals with sulfur and oxygen nucleophiles: direct versus allylic substitution

A remarkable regioselectivity difference in the Lewis-acid catalyzed reactions of 2-C-acteoxymethyl glycals with thiophenols and phenols has been observed. The reaction with thiophenols led to preferential formation of a new class of compounds viz. 2-C-arylthiomethyl glycals via direct attack at the C-2 side chain primary carbon bearing the leaving group. In contrast, phenols were reported to afford predominantly 2-C-methylene-O-aryl glycosides via allylic attack at the anomeric carbon. The observed results correlate well with the HSAB principle proposed earlier for similar type of reactions with simple glycals. In addition, formation of an unusual bis-thioarylated product in presence of an excess of thiophenol is also reported.     

On the regioselectivity for the Michael addition of thiols to unsymmetrical fumaric derivatives

The regiochemistry of the Michael addition of thiols to unsymmetrical fumaric derivatives was investigated. Conjugate addition of thiols to unsymmetrical fumaric diester was well controlled by the presence of lithium cation and one of the two possible regioisomers was prepared in a highly selective manner. Fumaric ester amides underwent the regioselective Michael addition that was controlled by the presence or absence of the base; either of the regioisomers was prepared as an almost diastereomerically pure form. The present control of the regiochemistry can be explained by the factors of change of active site for the addition by the coordination or non-coordination of proton or lithium cation to the carbonyls. To clarify the origin of the regioselectivity, the relative rates of the conjugate addition of thiol to acrylate derivatives were measured under competitive conditions. Ethyl acrylate reacted with thiol faster than tert-butyl acrylate and the rate difference was enhanced by the presence of lithium cation. In the presence of base, ethyl acrylate gave the adducts much faster than acrylamide, while under non-basic conditions acrylamide showed higher reactivity than the ester. This regioselectivity was also observed in the Michael/aldol reaction and multi-substituted γ-butyrolactones were prepared in a stereoselective manner. The thio groups introduced here served as a leaving group and a convenient stereoselective synthesis of β-, γ- and δ-lactams was developed.     

Modified palladium-catalyzed regioselective ortho-arylation of sp C-H bond substrates with a low catalyst loading

A novel and generally applicable system for ortho-arylation of a broad range of sp² C-H bond substrates such as arylated benzoxazoles, acylated anilines, and pyridines has been developed. The arylation was performed in trifluoroacetic acid (TFA) under air by using PdCl₂ as the catalyst with a low catalyst loading of 1 mol %. And it was found for the first time that the addition of weak base K₃PO₄ to the acidic solvent could remarkably enhance the reaction rate. The arylated products were isolated in moderate to good yields with high regioselectivity for the substrates containing a meta-substituent. This arylation is tolerant with various functional groups such as CH₃, CH₃O, CH₃CO, Br, and Cl.     

Expeditive synthesis of homochiral fused tri- and tetrazoles-piperazines from β-amino alcohols

N-Cyanomethyl and N-propargyl β-amino alcohols are chlorinated with SOCl₂ and treated with NaN₃ in DMSO. A substitution/cycloaddition process affords in good yields, with high diastereoselectivity and a regioselectivity depending on the substitution pattern of the starting amino alcohol, fused tri- and tetrazoles-piperazines. These heterocycles were further lithiated with n-BuLi at the benzylic position and reacted diastereoselectively with a range of electrophiles.     

Nucleophilic substitution in nitrofluorenones

The reaction of 2,4,5,7-tetranitrofluorenone with amines, thiols, and phenol in a polar aprotic solvent led to the preferable substitution of the nitro group in the position 2, and in the reaction of 2,4,7-trinitrofluorenone first the nitro group in the position 4 was replaced. The different regioselectivity is due evidently to the steric hindrances to the nucleophilic attack on the atom C⁴ caused by the nitro group in the position 5 of tetranitrofluorenone.