Novel indole syntheses by ring transformation of β-lactam-condensed 1,3-benzothiazines into indolo[2,3-b][1,4]benzothiazepines and indolo[3,2-c]isoquinolines

ortho-Nitrophenyl-substituted condensed 1,3-benzothiazines proved to be a useful core unit in indole syntheses under non-reductive conditions. Thus, the treatment of ortho-nitro-2-aryl-2a-chloro-4H-azeto[2,1-b][1,3]benzothiazin-1-ones with sodium methoxide in methanol provided indolo-1,4-benzothiazepines via a novel rearrangement. Through the sulfur extrusion reaction of indolo[2,3-b][1,4]benzothiazepines, further alkaloid-type indole derivatives, indolo[3,2-c]isoquinolines, were obtained. The structures of the new ring systems were determined by means of NMR spectroscopy.     

TARTROL-derived chiral phosphine–phosphite ligands and their performance in enantioselective Cu-catalyzed 1,4-addition reactions

By using (R,R,R,R)-2,3-dimethoxy-2,3-dimethyl-1,4-dioxane-5,6-bis-diphenylmethanol (TARTROL) as a chiral building block, a set of six modular phosphine–phosphite ligands (with a 1,2-phenylene backbone) were synthesized and evaluated in the Cu-catalyzed asymmetric 1,4-addition of Grignard reagents to cyclohexenone. Ligands with bulky substituents at the ortho- and para-positions to the chiral phosphite moiety were found to be the most selective affording the 1,4-addition products with enantioselectivities of up to 84% ee.     

AuCl-catalyzed reaction of ortho-alkynyl(oxo)benzene with benzenediazonium 2-carboxylate as a synthetic method towards anthracene, triptycene, and phthalazine derivatives

The AuCl-catalyzed benzannulation of ortho-alkynylphenyl ketones with benzenediazonium 2-carboxylate proceeded efficiently at 40 °C in (CH₂Cl)₂ and a variety of anthracene derivatives, having a ketone group at 9-position, were produced in good to high yields. On the other hand, the reaction of ortho-alkynylbenzaldehydes with benzenediazonium 2-carboxylate afforded triptycyl ketones. The reactions most probably proceed through the formation of a zwitterionic intermediate by the gold-induced electrophilic cyclization of ortho-alkynyl(oxo)benzenes, followed by the cycloaddition of benzyne. In contrast, when the above reaction was carried out at rt in 1,4-dioxane, phthalazine derivative was produced without the generation of benzyne.     

Investigation of electrochemically induced Michael addition reactions. Oxidation of some dihydroxybenzene derivatives in the presence of azide ion

In aqueous solution containing azide ion as a nucleophile, electrochemical oxidation of hydroquinone and some dihydroxybenzoic acids have been studied using cyclic voltammetry and controlled-potential coulometry. The voltammetric data show that electrochemically generated para and ortho-benzoquinones participate in Michael addition reactions with azide ions to form the corresponding diazido or diaminobenzoquinones. In this work, we have proposed various mechanisms for the electrode process and we report an efficient and one-pot method for the synthesis of 2,5-diazido-1,4-benzoquinone, 2,5-diamino-1,4-benzoquinone, 4,5-diamino-1,2-benzoquinone, and 2,3-diamino-5,6-dioxocyclohexa-1,3-dienecarboxylic acid based on the Michael reaction of electrochemically generated ortho and para-benzoquinones with azide ion in an undivided cell using an environmentally friendly reagent-less method in ambient conditions. An estimation of the observed homogeneous rate constant (k_obs) of the reaction of electrochemically generated para-benzoquinone with azide ion by the digital simulation method is also presented.     

The ortho effect: copper-catalyzed highly enantioselective 1,4-conjugate addition of diethylzinc to chalcones

The copper-catalyzed enantioselective 1,4-conjugate addition of diethylzinc to chalcones was investigated in the presence of a catalytic amount of N,P-ferrocenyl ligands with central and planar chirality under mild conditions (0 °C→rt). It was found that chalcones with ortho-substituents (from ortho-substituted benzaldehydes and acetophenone/substituted acetophenones) led to a dramatic improvement in the enantioselectivities. The (R)- and (S)-antipodes of the addition reaction were obtained with up to 92% ee after this transformation.     

A general synthesis of N-substituted 1,4-benzoxazine- and 1,4-benzothiazine-2-carboxylates via copper-catalyzed intramolecular amination of arylbromides

Starting from ortho-bromosubstituted phenoxyacetates or (phenythio)acetates and primary amines, various N-substituted 4H-1,4-benzoxazine- and 4H-1,4-benzothiazine-2-carboxylates were synthesized in moderate to high yields by using a Cu(I)-catalyzed Ullmann-type cyclization as a key step. The method is simple to operate, tolerates many functional groups and does not require any additives.     

Halogenation of N-substituted para-quinone monoimine and para-quinone monooxime esters: VI. Regular trends in chlorination and bromination of N-arylsulfonyl-1,4-benzoquinone monoimines alkyl-substituted in the quinoid ring

Reactions of halogens with N-arylsulfonyl-1,4-benzoquinone monoimines occur with the formation of a halogenonium ion that either transforms into a carbocation where the first halogen atom adds to the carbon in the ortho-position relative to the carbonyl carbon, or the halogenonium ion adds directly the second halogen atom.     

Base-promoted nucleophilic fluoroarenes substitution of CF bonds

With the use of KOH/DMSO as the superbase medium, the nucleophilic fluoroarene substitution for CF bonds is presented. The transformation proceeds smoothly with the use of fluoroarenes bearing not only electron-withdrawing group, but also electron-donating group and a variety of nucleophiles such as alcohols, phenols, amines, amides and nitrogen-heterocyclic compounds. The double nucleophilic substitution using ortho-difluoroarenes and nucleophiles bearing ortho-dinucleophilic groups results in the formation of 2,3-dihydro-1,4-benzodioxins, dibenzo[b,e][1,4]dioxins and 10H-phenoxazines in moderate to good yields.     

Novel porphyrin-quinazoline conjugates via the Diels-Alder reaction

Novel derivatives of meso-tetraphenylporphyrin with appended quinazoline moieties were synthesized, via the Diels-Alder reaction, between a 4-(porphyrinyl)pyrimidine ortho-quinodimethane and 1,4-benzoquinone, 1,4-naphthoquinone and N-(p-nitrophenyl)maleimide. The structure of one bis adduct was established by X-ray crystallography and mass spectrometry. We have unequivocally confirmed that the 2:1 adducts obtained from the reaction of pyrimidine-fused 3-sulfolenes with N-arylmaleimides have an open-chain structure and not a cyclooctapyrimidine structure, as previously published.     

Reactions of dibromotetrafluorobenzene derivatives with sodium phenoxide salts. Competing hydrodebromination and SNAr processes

1,2- and 1,3-dibromotetrafluorobenzene react with sodium phenoxide derivatives at sites para to ring bromine because these positions are activated by fluorine atoms ortho and meta to the site of nucleophilic substitution. Fluorine para to the site of nucleophilic attack is usually deactivating in nucleophilic aromatic substitution processes and this is reflected in the significantly reduced reactivity of 1,4-dibromotetrafluorobenzene which undergoes competing hydrodebromination processes to afford, primarily, 3-bromo-1,2,4,5-tetrafluorobenzene.     

A stereoselective synthesis of 3-substituted (S)-pyroglutamic and glutamic acids via OBO ester derivatives

(S)-Pyroglutamic acid is transformed to the Cbz-protected 4-methyl-2,6,7-trioxabicyclo[2.2.2] octane (OBO) ester. This ortho ester functionality is employed as a bulky steering group for stereoselective introduction of alkyl and aryl groups via 1,4-cuprate addition to 3,4-unsaturated pyroglutamates. After deprotection and ringopening, 3-substituted glutamic acids are obtained.     

Studies on bis(1′-ortho-carboranyl)benzenes and bis(1′-ortho-carboranyl)biphenyls

Reactions between the C,C′-dicopper(I) derivative of ortho-carborane and ortho-, meta- and para-diiodobenzene are reported. The reaction with 1,2-C₆H₄I₂ unexpectedly afforded 2,2′-bis(1′-ortho-carboranyl)biphenyl, [HCB₁₀H₁₀CC₆H₄]₂2, whereas reactions with 1,3- or 1,4-C₆H₄I₂ provided alternative routes to 1,3-bis(1′-ortho-carboranyl)benzene 3 and 1,4-bis(1′-ortho-carboranyl)benzene 4, respectively. The crystal structure of the biphenyl derivative 2 revealed significant distortions in the biphenylene framework attributable to the proximity of the two bulky carborane cages. UV absorption spectra and electrochemical data on 2 and 3 showed little electronic communication between the two carborane cages in either, and negligible π-conjugation between the two ortho-phenylene rings in 2. However, substantial evidence was found of electronic communication between the carborane cages via the para-phenylene bridge in 4. B3LYP/6-31G^∗ computations have been carried out on compounds 2 and 4, on 4,4′-bis(ortho-carboranyl)biphenyl 6 and on 1,2-bis(1′-ortho-carboranyl)benzene 7. Those on 2, 4 and 6 show the computed geometries to be in very good agreement with the experimental geometries: those on 7 allowed the reported molecular geometry of this compound to be revised and revealed a long cage C–C bond of 1.725(3) Å.     

β-Nitrostyrenes as electrophiles in Parham cyclization chemistry: reaction with o-lithiobenzonitrile

β-Nitrostyrenes react with o-lithiobenzonitrile, generated from the requisite aryl bromide at −100 °C by bromine-lithium exchange with n-butyllithium in THF, to afford 2-nitro-3-phenyl-3H-inden-1-ylamines resulting from 1,4-addition to the β-nitrostyrene followed by intramolecular capture of the resultant nitronate anion by the ortho-cyano functional group.     

Indium catalyzed solvent-free multicomponent synthesis of cytotoxic dibenzo[a,h]anthracenes from aldehydes, 2-hydroxy-1,4-naphthoquinone,and 2-naphthol

A series of dibenzo[a,h]anthracene derivatives were synthesized through a straightforward, one-pot protocol based on a three-component reaction with 2-hydroxy-1,4-naphthoquinone, aromatic aldehydes, and 2-naphthol as synthetic inputs, using InCl₃ a catalyst under solvent-free conditions. Most of the obtained ortho-quinonic adducts were cytotoxic against HEL and MCF-7 tumoral cell lines.     

Catalytic enantioselective synthesis of atropisomeric 2-aryl-4-quinolinone derivatives with an N–C chiral axis

In the presence of an (R)-MOP-Pd₂(dba)₃ catalyst, the reaction of ortho-tert-butylaniline with 2-bromophenyl arylethynyl ketone proceeded via a tandem amination (1,4-addition of aniline to an ynone and subsequent intramolecular Buchwald–Hartwig amination) to afford axially chiral N-(2-tert-butylphenyl)-2-aryl-4-quinolinone derivatives with moderate enantioselectivity (up to 72% ee).     

Equilibration of ortho- and para-hydrogen by homogeneous hydrogenation catalysts in solution; A test for the reversibility of hydrogen addition using Raman spectroscopy

para-Enriched hydrogen is converted into the ortho-para equilibrium mixture by tris(triphenylphosphine)rhodium chloride in toluene solution. The rotational Raman effect can be used to show that this equilibration occurs during the course of hydrogenation of cyclohexene by the above catalyst. The methanol solvate formed by reduction of 1,4-bis(diphenylphosphino)butanebicyclo[2.2.1] heptadienerhodium tetrafluoroborate also catalyses the ortho-para equilibration of hydrogen, in common with related cationic rhodium complexes. No equilibration occurs, however, during the course of hydrogenation of (Z)-α-benzamidocinnamic acid by cationic chelate rhodium complexes, including that derived from the chiral ligand (R,R)-1,2-bis(o-methoxyphenylphenyl)ethane (DIPAMP), thus demonstrating that addition of hydrogen to rhodium is irreversible.     

Assessment of the intramolecular C–H⋯X (X=F,Cl, Br) hydrogen bonding of 1,4-diphenyl-1,2,3-triazoles

The intramolecular six-membered C–H?X (X=F, Cl, Br) hydrogen bonding motif of halogen-substituted 1,4-diphenyl-1,2,3-triazole compounds has been assessed. Twelve triazole derivatives have been designed and prepared, which bear fluorine, chlorine or bromine atoms on the ortho- and/or para-positions of the benzene rings. ¹H NMR, X-ray crystallography, and DFT calculation investigations revealed that the ortho-fluorine, chlorine, and bromine atoms of the benzene ring on the C-4 of the triazole unit all can form six-membered C–H?X hydrogen bonding. In contrast, only fluorine forms similar, relatively stable intramolecular hydrogen bonding on the N-1 side of the triazole unit.     

The reaction of aromatic dialdehydes with enantiopure 1,2-diamines: an expeditious route to enantiopure tricyclic amidines

The condensation of enantiopure 1,2-diamines with terephthalaldehyde, isophthalaldehyde or 2-iodo-, 2-alkyl- or 2-aryl-1,3-benzenedialdehydes in toluene followed by treatment with NBS in dichloromethane gives direct access to enantiopure 1,4-, and 1,3-di(4,5-dihydro-1H-imidazol-2-yl)benzenes (diamidines). The condensation of o-phthalaldehyde, and other ortho-disubstituted aromatic dialdehydes, with enantiopure 1,2-diamines, without NBS, gives enantiopure 3,5-dihydro-2H-imidazol-[2,1]-isoindoles.     

Unprecedented N→C[1,4] Boc migration: synthesis of 3-carboxyl functionalized 7-azaindolo[2,1-c][1,4]benzoxazine ring system

Use of 1 equiv excess n-BuLi in synthesis of azaindolo[2,1-c][1,4]benzoxazine heterocycles furnished the corresponding 3-(tert-butyloxycarbonyl) derivatives presumably via an unprecedented intramolecular N→C[1,4] Boc migration. Thus, treatment of N-Boc-2-aminopicoline 1a with 3 equiv of n-BuLi at ?15 °C, to generate the dianion Li₂-1a, followed by the reactions with Weinreb amides 2a–h at ?40 °C, and then allowing the reaction mixture to warm upto rt in a controlled manner (?40 to 0 °C, 2 h; 0 °C to rt, 16 h) led to formation of a series of Boc-group migrated products 7a–h generally in good yield (～70% isolated yield). Surprisingly, going from cyclopentylene to cyclohexylene cases (2d–e to 2g–h), the desired [1,4] Boc migration was found to be a minor fate (yield ～20%). In these instances, N→ortho-C[1,3] Boc-migrated compounds 9g–h (to ortho-aryl position) were obtained as major products. Plausible mechanisms have been invoked for the formation of tetracyclic heterocycle 3a, as well as for the observed N→C[1,4] Boc-group migration phenomena supported by data from anion quenching experiments.     

Efficient synthesis of an androgen receptor modulator

An efficient synthesis of the androgen receptor modulator (R)-4a having an 8H-[1,4]oxazino[2,3-f]quinolin-8-one skeleton is described. Synthesis of this ring system, not readily accessible by classical Knorr cyclization methodology, was accomplished by an ortho-metallation strategy. Thus, lithiation of a pivaloyl-protected 7-amino-3,4-dihydro-1,4-benzoxazine using n-butyllithium allowed the introduction of a trifluoroacetyl group regioselectively at the 8-position. Subsequent Wittig reaction and acid catalyzed cyclization afforded the desired 8H-[1,4]oxazino[2,3-f]quinolin-8-one (R)-4a in very good overall yield from the corresponding benzoxazine.