2-(2-Hydroxyaryl)cinnamic amides: a new class of axially chiral molecules

The syntheses of several differently substituted amides formally derived from a chiral amine, either E-2-(2-hydroxyphenyl)cinnamic acid or both E- and Z-2-(2-hydroxynaphthyl)cinnamic acid, are reported. These molecules display a restricted rotation about the C₂-C_aryl bond. The barriers to rotation about the C₂-C_aryl bond were measured by the dynamic ¹H NMR and were found to vary between 11.8 and 24.5 kcal mol⁻¹, depending on the substitution. In particular, E-2-(2-hydroxynapthyl)cinnamic amides, displayed a high barrier to rotation (ΔG_c^‡=24.4 kcal mol⁻¹) and could be isolated in both diastereomerically pure forms at room temperature. The X-ray structure of one E-2-(2-hydroxynapthyl)cinnamic amide, was resolved, enabling for the determination of the absolute configuration of the chiral axis (aR).     

A synthesis of pyrrolo[2,1-a]isoquinolines through the reaction of activated acetylenes and isoquinoline in the presence of ethyl bromopyruvate

Isoquinoline reacts with ethyl bromopyruvate in the presence of dialkyl acetylenedicarboxylates or diaryloylacetylenes to produce dialkyl 1-(2-ethoxy-2-oxoacetyl)pyrrolo[2,1-a]isoquinoline-2,3-dicarboxylates or ethyl 2-[2,3-diaryloylpyrrolo[2,1-a]isoquinoline-1-yl]-2-oxoacetates in good yields.     

Synthesis and deprotonation of 2-(halophenyl)pyridines and 1-(halophenyl)isoquinolines

The ability of the 2-pyridyl and 1-isoquinolyl groups to direct metalation was studied in the benzene series. For this purpose, 2-(halophenyl)pyridines and 1-(halophenyl)isoquinolines were prepared. Interestingly, nucleophilic addition reactions on the azine ring were not observed under kinetic control using butyllithium, and the substrates were cleanly deprotonated on the benzene ring: the azine ring acidifies the adjacent hydrogen H2' (N-H2' interaction through space and/or inductive electron-withdrawing effect) and probably favors the approach of butyllithium (chelation). Under thermodynamic conditions using lithium dialkylamides, the presence of the azine group makes the lithio derivative at C2' more stable (chelation and/or inductive electron-withdrawing effect). This was evidenced in two ways: (1) syntheses of 2-halophenyllithiums (F, Cl, Br) substituted at C6 by a 2-pyridyl or 1-isoquinolyl group without elimination of lithium halide and (2) iodine migration from C2' to C4' when treating 2-(3-halo-2-iodophenyl)pyridines or 1-(3-fluoro-2-iodophenyl)isoquinoline with LTMP. Comparisons between the 2-pyridyl and fluoro units showed the latter was the stronger directing group for deprotonation.     

Three-component coupling reactions of isoquinolines, dimethyl acetylenedicarboxylate and indoles: a facile synthesis of 3-indolyl-1,2-dihydro-2-isoquinolinyl-2-butenedioate

A three-component coupling of isoquinolines, dimethyl acetylenedicarboxylate (DMAD) and indoles is achieved for the first time to produce dimethyl (E)-2-[1-(1H-3-indolyl)-1,2-dihydro-2-isoquinolinyl]-2-butenedioates in excellent yields and with high selectivity. The reaction proceeds smoothly at room temperature without a catalyst. Quinoline, DMAD and indole also undergo smooth coupling to furnish dimethyl (E)-2-[2-(1H-3-indolyl)-1,2-dihydro-1-quinolinyl]-2-butenedioate under similar conditions. This method is very useful to functionalize both indoles and aza-aromatic compounds in a one-pot operation.     

Iridium-catalyzed consecutive and enantioselective [2+2+2] cycloaddition of tetraynes and hexaynes for the construction of an axially chiral biaryl system

A chiral iridium complex catalyzed a consecutive and enantioselective [2+2+2] cycloaddition of polyynes to give axially chiral compounds. Intermolecular reaction of tetraynes, possessing aryl groups on their termini, with protected but-2-yne-1,4-diols gave C₂-symmetrical quateraryl compounds. Intramolecular reaction of hexaynes, possessing aryl or alkyl groups on their termini gave C₂-symmetrical biaryl compounds. The catalytic synthesis of a pentacene derivative with axial chiralities is also discussed.     

Axial [6,6′-(2,4-pentadioxy)]-1,1′-biphenyl-2,2′-diamine (PD-BIPHAM): practical synthesis and applications in asymmetric hydrogenation

A rapid, reliable, and atom-economical procedure for the novel axially biphenyl diamine, (R,R,S_ax)-PD-BIPHAM 1, has been developed successfully by using highly efficient central-to-axial transformation strategy. The attractive feature of this methodology is that no tedious resolution was needed. The effectiveness of this new chiral skeleton was initially demonstrated by highly enantioselective hydrogenation of α-dehydroamino acid esters.     

n-Butyl by-products in the syntheses of 2-(1- and 2-naphthyl)pyridines via lithiation

By-products in the syntheses of 2-(1- and 2-naphthyl)pyridines by successive treatments of 1- and 2-bromonaphthalenes with (a) n-butyllithium in ether and (b) pyridine are identified as 5-butyl-2-(1-naphthyl)pyridine and, tentatively, 5-butyl-2-(2-naphthyl)pyridine, respectively. It is proposed that these by-products result from reaction of intermediate compounds 1-lithio-2-naphthyl-1,2-dihydropyridines and 1-bromobutane.     

Stereoselective reactions. XXXII. Enantioselective deprotonation of 4-tert-butylcyclohexanone by fluorine-containing chiral lithium amides derived from 1-phenylethylamine and 1-(1-naphthyl)ethylamine

Enantioselective deprotonation of 4-tert-butylcyclohexanone was examined using 1-phenylethylamine- and 1-(1-naphthyl)ethylamine-derived chiral lithium amides having an alkyl or a fluoroalkyl substituent at the amide nitrogen. The lithium amides having a 2,2,2-trifluoroethyl group on the amide nitrogen are easily accessible in both enantiomeric forms, and were found to induce good enantioselectivity in the present reaction.     

Synthesis of 1-(2-naphthyl)dihydro- and 1-(2-naphthyl)-2-thiodihydrouracils and their transformations

1-(2-Naphthyl)dihydro- and 1-(2-naphthyl)-2-thiodihydrouracils were obtained from N-(2-naphthyl)--alanine derivatives. The thiodihydrouracil was converted to a dihydrouracil. Bromination of 1-(2-naphthyl)dihydrouracil gave (1-bromonaphthyl)dihydrouracil. 1-(2-Naphthyl)-2-oxo-, 1-(2-naphthyl)-2-thio-. and 1-(1-bromo-2-naphthyl)-2-oxohexahydro-pyrimidines were obtained.Translated from Khimiya Geterotsiklicheskikh Soedinenii. No. 12, pp. 1695–1697, December, 1971.     

Synthesis and reactions of some 6-(2-hydroxy-1-naphthyl)-1,2,4-triazines

4,5-Benzocoumaran-2,3-dione condenses with semicarbazide and thiosemicarbazide at the 3-position and the products obtained were converted to the corresponding 6-(2-hydroxy-1-naphthyl)-1,2,4-triazines. Reactions of these triazines with some reagents are described.     

Remote asymmetric trifluoromethylation induced by chiral sulfinyl group: synthesis of enantiomerically pure 1-(2-naphthyl)-2,2,2-trifluoroethanol

The reaction of 1-[(2,4,6-triisopropylphenyl)sulfinyl]-2-naphthaldehyde with (trifluoromethyl)trimethylsilane using tetramethylammonium fluoride gave trifluoromethylated compounds in high yield with high diastereoselectivity. Desilylation and subsequent recrystallization yielded the enantiomerically and diastereomerically pure trifluoroethanol, which afforded chiral 1-(2-naphthyl)-2,2,2-trifluoroethanol after removal of the sulfinyl group.     

Enantioselective synthesis of 2-arylpiperidines from chiral lactams. A concise synthesis of (-)-anabasine

Cyclodehydration of achiral or racemic aryl-delta-oxoacids with (R)-phenylglycinol stereoselectively affords chiral non-racemic bicyclic lactams, from which the enantiodivergent synthesis of (R)- and (S)-2-phenylpiperidine, the diastereodivergent synthesis of cis- and trans-3-ethyl-2-phenylpiperidine, and the enantioselective synthesis of the piperidine alkaloid (-)-anabasine is reported.     

Dynamic Kinetic Resolution of 2-(Quinolin-8-yl)Benzaldehydes: Atroposelective Iridium-Catalyzed Transfer Hydrogenative Allylation

An atroposelective Ir-catalyzed dynamic kinetic resolution (DKR) of 2-(quinolin-8-yl)benzaldehydes/1-naphthaldehydes by transfer hydrogenative coupling of allyl acetate is disclosed. The allylation reaction takes place with simultaneous installation of central and axial chirality, reaching high diastereoselectivities and excellent enantiomeric excesses when ortho-cyclometalated iridium-DM-BINAP is used as the catalyst. The racemization of the substrates occurs through a designed transient Lewis acid-base interaction between the quinoline nitrogen atom and the aldehyde carbonyl group.     

A new, modular approach towards 2-(1-hydroxyalkyl)oxazolines, effective bidentate chiral ligands

Addition of β-hydroxyisonitriles towards aldehydes gives rise to hydroxyalkyl oxazolines, an interesting class of bidentate chiral ligands. This concept allows a very easy ligand tuning and optimization of the ligand structure as illustrated in a first example.     

3-Cyanopyridine-2(1H)-thiones and 3-cyano-2-(methylthio)pyridines in the synthesis of substituted 3-(aminomethyl)pyridines

The reactions of substituted 3-cyanopyridine-2(1H)-thiones and 3-cyano-2-(methylthio)pyridines with lithium aluminum hydride in anhydrous diethyl ether afforded the corresponding 3-aminomethyl derivatives, which were used in the synthesis of the corresponding amides.     

Regioselective synthesis of 2-(2-hydroxyaryl)pyridines from the reactions of benzynes with pyridine N-oxides

By modifying the conditions from those in Larock's reported synthesis of 3-(2-hydroxyaryl)pyridines from benzynes, and pyridine N-oxides, we altered the regioselectivity of the reaction toward an efficient synthesis of 2-substituted pyridines. The presence of ethyl propiolate altered the regioselectivity to afford 3-substituted pyridine products instead. We conducted appropriate control experiments that enable a full understanding of the mechanism.