Metalation of sulfoxides in the benzodiazine series. Diazines. Part 44

The metalation of 12 benzodiazines sulfoxides was tested. This reaction was effective with 3-sulfinylcinnolines, 5-phenylsulfinyl-2-tert-butylquinazoline and 8-tert-butylsulfinyl-2-tert-butyl-4(3H)-quinazolinone.     

Synthesis of Chiral Benzofuran-Derived β-Amino Esters Induced by N-tert-Butanesulfinamide

The benzofuran skeleton is commonly found in a wide variety of natural products that display a wide range of biological activities. For this reason, benzofuran has a high potential for use as a scaffold in both chemical and pharmaceutical syntheses of natural products. This work describes the development of a novel asymmetric synthetic method of benzofuran-derived β-amino esters via K₂CO₃-promoted domino reactions of ortho-hydroxyl aromatic N-tert-butylsulfinyl imines and diethyl bromomalonate. A small library of target compounds was prepared under optimized reaction conditions in moderate to good yields with high distereoselective and enantioselective properties. The newly generated chiral carbon center was of an (S)-configuration as determined by x-ray diffraction.     

Metalation of diazines. VI. Metalation of pivaloylaminopyrazine and N-t-butylpyrazinamide. Unusual regioselectivity in the metalation reaction

Metalation of pivalamidopyrazine and N-t-butylpyrazinamide were studied. For pivalamido pyrazine the yields were poor and some addition products were isolated. The metalation of t-butylpyrazinamide was successful and a curious regioselectivity was highlighted.     

Stereoselective synthesis of 3-substituted tetrahydroisoquinolines from phthalan and chiral N-sulfinylimines

The reaction of the dianionic intermediate [resulting from the reductive opening of phthalan (1) with lithium] with chiral N-tert-butylsulfinyl aldimines 3 in the presence of ZnMe₂ gives, after hydrolysis, N-tert-butylsulfinyl amino alcohols 4 with high diastereoselectivity. Successive treatment of compounds 4 with hydrogen chloride in methanol, thionyl chloride in chloroform and sodium hydroxide yields 3-substituted tetrahydroisoquinolines 6.     

Use of sulfur derivatives as an ortho directing group for the metalation of diazines. Metalation of diazines. XVIII

The metalation of thioethers, methyl and phenyl sulfoxides and sulfones of pyrazine and pyridazine has been performed. Methyl sulfoxides and sulfones were first metalated on the methyl group. The ortho directing effect of thioethers, sulfoxides and sulfones have been compared with the methoxy group. The sulfoxides were shown to be very good ortho directing groups.     

Cascade One-Pot Synthesis of Orange-Red-Fluorescent Polycyclic Cinnolino[2,3-f]phenanthridin-9-ium Salts by Palladium(II)-Catalyzed C−H Bond Activation of 2-Azobiaryl Compounds and Alkenes

Quaternary ammonium salts were synthesized in moderate to good yields through double oxidative C−H bond activation on azobenzenes. The mechanism of the highly regioselective reaction of 2-azobiaryls with alkenes to give orange-red-fluorescent cinnolino[2,3-f]phenanthridin-9-ium salts and 15H-cinnolino[2,3-f]phenanthridin-9-ium-10-ide is proposed to involve ortho C−H olefination of the 2-azobiaryl compound with the alkene, intramolecular aza-Michael addition, concerted metalation–deprotonation (CMD), reductive elimination, and oxidation.     

Base-promoted diastereoselective addition of nitromethane and nitroethane to N-tert-butylsulfinyl imines: synthesis of N-protected α-amino acids and amino ketones

The reaction of N-tert-butylsulfinyl imines with nitromethane or nitroethane in the presence of NaHCO₃ under solvent-free reaction conditions gave β-nitro amine derivatives with reasonable levels of diastereoselectivity. Enantioenriched N-tert-butylsulfinyl protected α-amino acids or α-amino ketones are accessible upon oxidation of the adducts derived from nitromethane or nitroethane, respectively.     

Metalation of unsaturated polymers by using activated organolithium compounds and the formation of graft copolymers. II

Polybutadiene was successfully metalated by use of tert-butyllithium activated with alkoxides of Group I metals without chain degradation. The metalated polymer was grafted with styrene and 1,3-butadiene to give novel graft copolymers of varying microstructure. This metalating system was found to be highly efficient; however, its catalyst effectiveness is less than that of organolithium-TMEDA metalation agent.     

Metalation in hydrocarbon solvents: the mechanistic aspects of substrate-promoted ortho-metalations

The methoxy-substituted aromatic reagents 1,2- and 1,3-dimethoxybenzene (1,2-DMB and 1,3-DMB) and 1,2,4-trimethoxybenzene (1,2,4-TMB) each undergo directed ortho-metalation in high yield in n-BuLi/hydrocarbon media without the aid of a catalyst. These reactions, coined ‘substrate-promoted ortho-metalations’, proceed with the methoxy aromatic substrate functioning as both the directing metalation group (DMG) and as the deoligomerization agent. Evidence that the substrates themselves serve to deoligomerize n-BuLi comes from ¹³C NMR. The relative extent of metalated product formed as a function of time for each of the three aromatics directly correlates with the substrate's time-dependent ability to coordinate to n-BuLi as measured by ¹³C NMR. The interpretation of NMR results from experiments involving 1,2,4-TMB is consistent with the metalation proceeding via the activated complex [(1,2,4-TMB)₂·(n-BuLi)₂]. Finally, conclusions from solubility experiments are that for every substrate-promoted metalation investigated, a precipitate forms in the hydrocarbon solvent, and this precipitate mostly contains the ortho-lithiated aryl intermediate.     

Directed Metalation Linked to Transition Metal Catalyzed Cascade Reactions: Two Total Syntheses of Plicadin,the Alleged Coumestan from Psoralea plicata

The oxygen-rich heterocyclic compound 1 —which was proposed to be the structure of plicadin, the alleged naturally occurring coumestan from the herb Psoralea plicata—was synthesized by the rational combinations of directed ortho and remote metalation reactions with cascades of Negishi, Sonogashira, Castro–Stephens, and carbamoyl Baker–Venkataraman reactions.     

The convergent syntheses of pyrazinyl and quinoxalinyl phenylmethanones from 2-lithio pyrazines and quinoxalines

Pyrazines and quinoxalines bearing 2-substituents that direct ortho metalation reacted with lithium 2,2,6,6-tetramethylpiperidide to produce 2-substituted-3-lithiopyrazines and quinoxalines. These lithio reagents reacted with N-methoxy-N-methylbenzamide to give good to moderate yields of 3-substituted pyrazinyl or quinoxalinylphenylmethanones. The 3-methylthio substituents of some ketone products were oxidized to methylsulfonyl groups that were susceptible to nucleophilic displacement.     

Metalation of o-methylanisole (o-MA); an optional-site selectivity reassessment

‘Deficiency catalysis’ is the concept applied to metalation chemistry that increments of TMEDA or an equivalent or two of an ether activate alkyllithiums in hydrocarbon media. Amplification of this concept to conflicting reports of α- and ortho-metalation of ortho-methylanisole (o-MA) is explored. Both regioselective metalations were realized in selectivity ratios of >7:1 for the desired isomers. Some rationale is provided for the various selectivities. These results are at variance with prior results and interpretations thereof found in the literature.     

Insights into the Metalation of Benzene and Toluene by Schlosser’s Base: A Superbasic Cluster Comprising PhK,PhLi, and tBuOLi

The metalation of benzene by Schlosser’s base (nBuLi/tBuOK) occurs smoothly in THF at low temperatures to afford a discrete mixed‐metal Li₂K₄ cluster that contains phenyl anions and tert‐butoxide. The aggregate itself exhibits superbasic behavior by metalating toluene. The delocalized benzyl anion obtained this way π bonds to potassium counterions, thereby creating a 2D coordination polymer.     

Synthesis of ortho-substituted aminopyridines. Metalation of pivaloylamino derivatives

The three isomeric pivaloylaminopyridines were lithiated in more than 80% yields. Aminopyridine derivatives were treated by 2.5-3 equivalents of the complex BuLi-TMEDA at −10° in diethyl ether. Reaction of the lithiated species with various electrophiles afforded a number of ortho-substituted pivaloylaminopyridines in good yields. Secondary pyridine alcohols were oxidized to the corresponding aminopyridyl ketones. Pyridopyrimidines, benzonaphthyridines as well as an analogue of the natural antitumor alkaloid ellipticine has been synthesized showing the versatility of the method.     

Application of the ortho-lithiation-cyclization strategy to N-benzyl-and N-phenethylamine derivatives

The ortho-lithiation-cyclization of iodinated N,N-diacylphenethylamines provides a convenient method for the preparation of 2-(2-acetoamidoethyl)acetophenones and 2-(2-benzamidoethyl)benzophenones, which could be easily transformed into dihydroisoquinolines. By contrast, the N-ethylamino, N-acetylamino, and N-trimethylsilylamino moieties studied as ortho-directing groups provide poor assistance to the metalation of N-benzyl- and N-phenemylamines and the corresponding isoindolone or isoquinolone derivatives are obtained in low yields.     

Synthesis of chiral β-3-amino-2-hydroxyalkanoates and 3-alkyl-3-hydroxy-β-lactams by double asymmetric induction

Reactions of chiral (2S)-enolates of dioxolan-4-ones, derived from lactic, mandelic, and phenyllactic acids, with aliphatic (S_S)- and (S_R)-tert-butylsulfinyl aldimines afforded conformationally restrained C2-disubstituted N,O-orthogonally protected 3-amino-2-hydroxyalkanoates in the form of N-sulfinyl protected 1′-aminodioxolan-4-ones. The product distribution showed that there is significant kinetic selectivity, due to the presence of ‘matched’ and ‘mismatched’ components, between the (S)- or (R)-tert-butylsulfinyl aldimines and the (2S)-enolates of the 1,3-dioxolan-4-ones. Selective methoxide-induced removal of the acetal group of the N-sulfinyl-1′-aminodioxolanones yielded the corresponding N-sulfinyl protected methyl alkanoates. In addition, the selective acid-induced removal of the sulfinyl group of the N-sulfinyl-1′-aminodioxolanones provided the corresponding N-unprotected 1′-aminodioxolanones, whose base-induced cyclization afforded the corresponding β-lactams.     

One-pot synthesis of carbohydrate thionolactones from 1-thiosugars

A general and efficient one-pot method for the synthesis of carbohydrate thionolactones from the corresponding 1-thiosugar is described involving the formation of an intermediate glycosyl S-tert-butyl thiosulfinate in situ by treatment of a thiol with commercially available tert-butylsulfinyl chloride in toluene at room temperature, followed by thermolysis. The method can also be used to generate reactive thioaldehydes and thioketones directly from thiols, which can be trapped in situ with a suitable diene.     

On the mechanism and diastereoselectivity of 2,3-dihydrobenzofuran formation from sulfinylbenzoquinones and 2-trimethylsilyloxyfuran

A mechanistic study of the reactions between 2-trimethylsilyloxyfuran 1 and (SS)-2-(arylsulfinyl)-1,4-benzoquinones 2a and 2b, giving rise to the diastereoselective formation of [3aS,8bS,SS]-3a,8b-dihydro-7-hydroxy-8-(arylsulfinyl)furo[3,2-b]benzofuran-2(3H)-ones 3a and 3b, is reported. The detection and ¹H NMR characterization of several precursors of 3a and 3b accounts for a Michael-type initial reaction which dictates the final diastereoselection of the process. A significant improvement of the stereoselectivity (up to 96% de) in the formation of the tert-butylsulfinyl substituted derivative 3c was achieved by using 2-(tert-butylsulfinyl)-1,4-benzoquinone 2c as the starting quinone.     

Directed Remote Lateral Metalation: Highly Substituted 2‐Naphthols and BINOLs by In Situ Generation of a Directing Group

A general synthesis of highly substituted 2‐naphthols based on a new carbanionic reaction sequence is demonstrated. The reaction exploits the dual nature of lithium bases consisting of consecutive ring opening of readily available coumarins with either LiNEt₂ or LiNiPr₂ into Z‐cinnamamides, thus generating a directing group in situ and allowing, by conformational freedom, a lateral directed remote metalation for ring closure to give the aryl 2‐naphthols in good to excellent yields. These transformations can be combined to provide a more efficient one‐pot process. Mechanistic insight into the remote lateral metalation step, demonstrating the requirement of Z‐cinnamamide, is described. Application of this methodology to the synthesis of highly substituted 3,3′‐diaryl BINOL ligands is also reported.     

Iridium‐Catalyzed C?H Activation versus Directed ortho Metalation: Complementary Borylation of Aromatics and Heteroaromatics

Systematic studies are presented demonstrating the complementarity of directed ortho metalation (DoM) and Ir‐catalyzed strategies for the provision of borylated aromatics and their subsequent Suzuki–Miyaura coupling reactions. A new concept, the use of the TMS group, readily introduced by DoM, as a latent regiodirective moiety to overcome the otherwise problematic production of isomeric borylated product mixtures is presented. Additional electrophile‐induced ipso‐deborylation and DoM reactions of the Bpin products are described.