Improved solid-phase synthesis and study of arylopeptoids with conformation-directing side chains

The development of an improved methodology for iterative solid-phase synthesis of para- and meta-arylopeptoids (oligomeric N-substituted aminomethyl benzamides) using benzoyl chloride building blocks is described. This methodology has enabled the synthesis of arylopeptoids with tert-butyl and phenyl side chains, which allows for complete control over the amide conformation: the tert-butyl results in a 100% cis amide conformation while the phenyl side chain results in a 100% trans amide conformation. The method has furthermore enabled the first synthesis and preliminary conformational studies of arylopeptoids bearing (S)-N-(1-phenylethyl) side chains.     

Steric effect of substituents in haloarenes on the rate of cross-coupling reactions

The relative reactivity of ortho- and para-methyl-substituted iodoarenes in the Sonogashira reaction and palladium-catalyzed methoxycarbonylation, as well as of similarly substituted bromoarenes in the Suzuki reactions and cobalt-catalyzed methoxycarbonylation, was studied. Introduction of a methyl group into the para position of aryl halide slows down the cross-coupling. o-Methylhaloarenes are less reactive in palladiumcatalyzed reactions as compared to both unsubstituted haloarene and para-substituted analog. The presence of a methyl group in the ortho position with respect to the reaction center accelerates cobalt-catalyzed methoxycarbonylation.     

Asymmetric synthesis of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates

This study describes general methods for the enantioselective syntheses of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates through dirhodium tetracarboxylate-catalysed asymmetric cyclopropanation of vinyl heterocycles with aryl- or heteroaryldiazoacetates. The reactions are highly diastereoselective and high asymmetric induction could be achieved using either (R)-pantolactone as a chiral auxiliary or chiral dirhodium tetracarboxylate catalysts. For meta- or para-substituted aryl- or heteroaryldiazoacetates the optimum catalyst was Rh₂(R-p-Ph-TPCP)₄. In the case of ortho-substituted aryl- or heteroaryldiazoacetates, the optimum catalyst was Rh₂(R-TPPTTL)₄. For a highly enantioselective reaction with the ortho-substituted substrates, 2-chloropyridine was required as an additive in the presence of either 4 Å molecular sieves or 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). Under the optimized conditions, the cyclopropanation could be conducted in the presence of a variety of heterocycles, such as pyridines, pyrazines, quinolines, indoles, oxadiazoles, thiophenes and pyrazoles.

The dirhodium tetracarboxylate-catalysed asymmetric cyclopropanation has been applied to the enantioselective syntheses of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates.     

Synthesis of bis(indole)-1,2,4-triazinones

A facile method for the synthesis of para- and meta-substituted bis(indole)-1,2,4-triazinones is presented. Our approach to access these triazinones involves a cyclocondensation reaction between amidrazone and ketoester functionalities. The structures of these interesting compounds were established unambiguously by X-ray crystallography.     

Synthesis of aryltriethoxysilanes via rhodium(I)-catalyzed cross-coupling of aryl electrophiles with triethoxysilane

The general and efficient silylation of aryl halides has been developed utilizing triethoxysilane and a rhodium catalyst. The substrate scope is broad and includes ortho-, meta-, and para-substituted electron-rich and -deficient aryl iodides. In addition, the silylation of aryl bromides and fluoroalkanesulfonates proceeded in the presence of tetra-n-butylammonium iodide.     

Tandem molecular rearrangement in the alkylation of phenol with camphene

The alkylation of phenol with camphene in the presence of boron trifluoride in glacial acetic acid was accompanied by tandem molecular rearrangement with formation of a mixture of ortho- and para-substituted phenols having 1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yl and 5,5,6-trimethylbicyclo[2.2.1]hept-exo-2-yl substituents. The same products were obtained by rearrangement of 1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yloxybenzene under analogous conditions. Similar reactions performed in the presence of aluminum phenoxide as catalyst resulted in predominant formation of the corresponding ortho-substituted phenols.     

Effects of acyl donor type, catalyst type, and reaction conditions on the activity and selectivity of Friedel-Crafts acylation

Acylation of anisole and 3-methylanisole was performed with several acylating reagents (acetylation by AcCl and Ac₂O and bromoacetylation by BrAcCl and (BrAc)₂O) over different solid acid catalysts. The reaction conditions were optimized with respect to the acylation reagent, overall yield, solid acid catalyst, and the products selectivities. While acylation of anisole with acetyl chloride or acetic anhydride resulted in its full conversion to para-substituted acetophenone, the use of bromoacetyl bromide or bromoacetic anhydride yielded also the ortho-substituted product. Acylation of 3-methylanisole also yielded both para- and ortho-substitutions, and the products distribution was affected by the reaction conditions and catalyst type. It was found that while more acidic catalysts (caesium salt of heteropolyacid and zeolites) were the most active towards anisole acylation, the most active catalysts for the acylation of 3-methylanisole were ion-exchange catalysts. Employing HY-740 zeolite resulted in the highest ortho-selectivity in the acylation of anisole with bromoacetyl bromide and bromoacetic anhydride and in the acylation of 3-methylanisole with acetic anhydride.     

Oxidation with Fremy's salt—VIII : Peri-effect of a group located at the C5 position of 1-naphthol and related compounds

It has been shown by a series of experiments on 5-alkyl, 5-halo-, and other 5-substituted 1-naphthol derivatives that the product ratio of the ortho- and para-naphthoquinones formed on oxidation with Fremy's salt is controlled by the bulkiness of the C₅-substituent.     

Manganese triacetate oxidation of methyl 1-hydroxy-2-naphthalene carboxylates

Manganese-triacetate mediated oxidation of 1-hydroxy-2-napthalene carboxylates in benzene under anhydrous conditions delivers the dimerized product. However, acetoxylation on the ortho- or para-position, or oxidation to quinones occurs on the 1-hydroxy-3-substituted 2-napthalene carboxylates depending on the nature of the substituents when the reaction is carried out in a mixture of acetic acid/acetonitrile.     

Urea as ammonia equivalent in aryl halides amination catalyzed by palladium complexes

Urea reaction with nonactivated aryl bromides and chlorides under catalysis with palladium complexes led to the formation in 65–95% yield of triarylamines from para-and meta-substituted aryl halides and of diarylamines from ortho-isomers.     

Remarkable regioselectivities in the course of the synthesis of two new Luotonin A derivatives

Ethyl 4-oxo-3,4-dihydroquinazoline-2-carboxylate reacts selectively with trimethylaluminium-activated 2-amino- or 4-aminobenzoic acid ethyl esters to give the corresponding anilides without self-condensation of the aminobenzoate building blocks. After propargylation, the quinazolinones were treated with Hendrickson's reagent, but only the para-substituted ester was found to undergo the expected [4 + 2] cycloaddition reaction, affording a new Luotonin A derivative. A different regioselectivity was observed with the ortho-substituted ester which affords a benzoxazinone under identical conditions. When the ester group in the ortho-substituted intermediate is replaced with a nitrile function, the outcome of the reaction with Hendrickson's reagent depends on the absence or presence of a base (DBU), yielding either a triphenylphosphonium-substituted iminobenzoxazine or a 4-cyano-substituted Luotonin A derivative.     

Vapour pressures and enthalpies of vaporization of a series of substituted phenyl isobutyl ethers

Molar enthalpies of vaporization of 2-Br-phenyl isobutyl ether, 3-Br-phenyl isobutyl ether, 4-Br-phenyl isobutyl ether, and 2-Br-4-Me-phenyl isobutyl ether were obtained from the temperature dependence of the vapor pressure measured by the transpiration method. The measured data sets were successfully checked for internal consistency. The values of enthalpies of vaporization and vapor pressures of ortho-, meta-, and para-substituted benzenes are discussed in the context.     

Solid-phase synthesis of 1,5-substituted 2-(N-alkylamino)-imidazolidin-4-ones

The solid-phase synthesis of 1,5-substituted 2-(N-alkylamino)-imidazolidin-4-one from resin-bound amino acid is described. Using a guanidinylating reagent in solution to form the guanidine moiety instead of resin-bound carbodiimide, an N-alkyl substitution is introduced specifically onto the 2-amino position. Combined with an alkylation step of the resin-bound amino acid prior to guanidinylation, all desired substitutions of the final products are achieved without racemization at chiral centers. This reaction sequence is also compatible with a variety of protected amino acid side chains.     

Relative substituent position on the strength of π-π stacking interactions

It was observed that the relative position of the arene substituents has a profound influence on the strength of π-π stacking in the 9-benzyl-substituted triptycene system. A new series of model compounds (3a-i) capable of revealing quantitatively π-π stacking interactions was studied. This series of compounds (3a-i) has an ortho-substituted methyl group in one of the two interacting arenes and the syn/anti ratios were determined and compared to a series previously studied compounds (4a-i) that have a para methyl group on the corresponding arene. A greater than 50% increase in the strength of π-π stacking interactions was observed with the methyl group in the ortho position comparing to that in the para position. No difference in π-π stacking interactions was observed when the other aromatic ring was a pentafluorobenzoate group.     

Synthesis and structure characterization of unsymmetrical oxacalix[2]benzene[2]pyrazines

The synthesis of two unsymmetrically linked oxacalix[2]benzene[2]pyrazines (1 and 2) is described. X-ray single crystal structure analysis revealed a highly distorted 1,3-alternate conformation of compound 1 (containing ortho- and meta-diphenol components) and a distorted boat conformation of compound 2 (containing meta- and para-diphenol components). Oxacalix[2]benzene[2]pyrazine containing both ortho- and para-diphenol components was not obtained via similar synthetic strategy.     

One-Pot Generation of Benzynes from Phenols: Formation of Primary Anilines by the Deoxyamination of Phenols

Benzynes were selectively generated in situ from phenols and trapped regioselectively with potassium hexamethyldisilazide to form primary anilines following acidic workup. The direct conversion of a phenolic hydroxyl group into a free amino group is a useful method for the preparation of primary aryl amines that are hard to synthesize by using coupling reactions involving phenol derivatives with ammonia. Whereas reactions of ortho- and meta-substituted phenols produced meta-substituted anilines exclusively, those of para-substituted phenols provided ortho-silylanilines.     

Use of two-parameter correlations for studying the radical reactivity of aromatic compounds

Two-parameter equation correlations are reported for radical reactions of aromatic compounds. In these correlations polar and resonance substituent constants identical with the substituent constants of aliphatic compounds were used. The equations correlate the rate constants for H abstraction reactions and for the addition of a variety of free radicals to the ortho-, meta-, and para-substituted aromatic compounds. Besides, they correlate parameters of the spectra for substituted aromatic radicals. The correlations show that the effects of para substituents on the reactions studied are nearly entirely resonance effects, whereas for the meta- and ortho-substituted compounds polar (inductive) effects become essential. Application of the two-parameter correlations permits also to determine the structure of transition states (σ or π-complex) in free-radical reactions.     

A convenient and efficient one pot synthesis of unsymmetrically substituted p-terphenyls via a phosphine-free double Suzuki cross-coupling protocol using 1,4-dibromo-2-nitrobenzene as the substrate

A synthetic procedure has been developed to enable the sequential regio-selective Suzuki-Miyaura cross-coupling of 1,4-dibromo-2-nitrobenzene with a variety of arylboronic acids. The first Suzuki coupling step, using a phosphine-free palladium catalyst at room temperature, gave selective coupling at the position ortho to the nitro group, opening a convenient synthetic route to unsymmetrical para-terphenyls. The bromobiaryl product was then subjected directly to the second coupling step, in situ, using preferred aryl-boronic acids to give by this one-pot batch procedure unsymmetrically substituted para-terphenyls in excellent overall isolated yields. This methodology should be particularly suited for the generation of targeted chemical libraries, as well as for the synthesis of precursors of biologically active compounds or natural products which are derived from the unsymmetrical para-terphenyl core.     

Photochromism of new unsymmetrical isomeric diarylethenes bearing a pyridine group

A new class of unsymmetrical isomeric diarylethenes bearing a terminal pyridine group was synthesized and their structures were determined by single-crystal X-ray diffraction analysis. The effects of the nitrogen atom position in the pyridine group on their properties including photochromism, acidchromism, and fluorescence were investigated systematically. Among the three isomeric derivatives, the cyclization quantum yield and the absorption maxima of the ortho-substituted diarylethene were the biggest, while the fluorescence quantum yield of the para-substituted diarylethene was the biggest. Furthermore, the three isomeric diarylethenes exhibited multi-addressable switching behaviors by the stimulation of acid/base and light. Addition of trifluoroacetic acid to solutions of these diarylethenes produced the protonated derivatives, which also showed excellent photochromic behaviors, but only the para-substituted diarylethene exhibited a notable color change of solution from crimson to violet. The results revealed that the effects of the nitrogen atom position in the terminal pyridine group played a very important role during the process of photoisomerization for these isomeric diarylethene derivatives.