Synthesis of β-homophenylalanine derivatives by Negishi cross-coupling reactions

Three approaches to the synthesis of β²-homophenylalanine derivatives using Negishi cross-coupling reaction are reported. In the first two approaches, two protected α-iodomethyl-β-amino esters are each converted into the corresponding organozinc iodides, which then undergo Pd-catalysed cross-coupling with aromatic halides to give β²-homophenylalanine derivatives, and the X-ray crystal structure of one product is reported. Alternatively, Negishi cross-coupling of the zinc reagent derived from N-benzyl 3-iodomethyl azetidin-2-one and aryl halides gave 3-benzylazetidin-2-ones, masked β²-homophenylalanine derivatives. The X-ray crystal structure of 1-benzyl-3-[(p-toluenesulfonyloxy)-methyl]-azetidin-2-one confirms the structural assignment.     

Negishi cross-coupling reactions of α-amino acid-derived organozinc reagents and aromatic bromides

The Negishi cross-coupling reaction of organozinc iodides derived from α-amino acids with aromatic bromides to give substituted phenylalanine derivatives is described, using either Pd(OAc)₂ or Pd₂(dba)₃ in combination with P(o-Tol)₃ as catalyst in DMF at 50 °C. Similar results are obtained using Pd[P^tBu₃]₂ as catalyst. The difference in reactivity displayed between aryl iodides and bromides (ArI>ArBr) has been utilised in a short synthesis of an unsymmetrical, orthogonally protected para-phenylene bis-alanine derivative.     

Synthesis of polysubstituted isoquinolines through cross-coupling reactions with α-alkoxytosylhydrazones

A Pd-catalyzed cross-coupling reaction of α-alkoxytosylhydrazones with sulfonates derived from salicyl aldehydes gives rise to protected 1,5-dicarbonyl compounds. Treatment with ammonium hydroxide readily transforms these alkenes into isoquinolines with diverse substitution patterns at positions 3 and 4. In a similar way, the employment of o-cyanononaflates in the coupling reaction, followed by treatment with an organometallic, provides isoquinolines that incorporate substitution also at position 1. The combination of both approaches represents a versatile method for the preparation of isoquinolines substituted at any position of the heterocyclic ring.     

Negishi coupling of 2-pyridylzinc bromide—paradigm shift in cross-coupling chemistry?

The efficient cross-coupling of 2-pyridylzinc bromide with functionalized aryl halides has been accomplished by a simple and highly efficient protocol. To the best of our knowledge, we report the first shelf life study of 2-pyridylzinc bromide which confirms the excellent stability of this compound and underlines the synthetic value of organozinc reagents in the cross-coupling reactions of sensitive heterocyclic nucleophiles on academic and commercial scale.     

Synthesis of chiral N,N′-disubstituted 1,2-benzenediamines from o-dibromobenzene

Palladium-catalyzed amination of o-dibromobenzene provided chiral N,N′-disubstituted 1,2-benzenediamines in good to excellent yields. The amination was executed stepwise and in one pot to give unsymmetrically and symmetrically substituted 1,2-benzenediamines. Incorporation of chiral primary amines was possible without racemization using catalytic Pd₂dba₃–BINAP.     

Synthesis of 3-acylindoles via decarboxylative cross-coupling reaction of free(N–H) indoles with α-oxocarboxylic acids

A convenient and general method for acylation of free(N–H) indoles via palladium-catalyzed decarboxylative cross-coupling reaction was developed. This process provided a useful method for the preparation of diverse 3-acylindoles in high yields utilizing a reaction with readily accessible reactants under mild conditions.     

Microwave-assisted palladium-catalyzed cross-coupling reactions between pyranoid glycals and aryl bromides. Synthesis of 2′-deoxy C-aryl-β-glycopyranosides

Under microwave irradiation, perbenzylated pyranoid glycals were coupled with aryl bromides in the presence of 5% mol palladium(II) acetate in dimethylformamide to produce 2′,3′-unsaturated C-aryl-α-glycopyranosides in a rapid and stereospecific manner. The synthetic applicability of the method was further demonstrated by converting the resulting C-aryl glycosides to 2′-deoxy C-aryl-β-glycopyranosides through oxidation mediated by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and stereoselective reduction.     

Preparation of polymer-supported phosphine from ferrocene for palladium-catalyzed Suzuki-Miyaura cross-coupling reactions

Polymer-supported phosphine ligand 3b derived from ferrocene was prepared,and applied in palladium-catalyzed Suzuki- Miyaura reactions.A range of aryl bromides can couple with phenylboronic acid to obtain corresponding biaryls in excellent yields. The recycling of the polymer-bound catalyst was tested without adding palladium.     

Friedl?nder synthesis of chiral alkyl-substituted 1,10-phenanthrolines.

The synthetic scope of the Friedl?nder condensation in the preparation of chiral alkyl-substituted 1,10-phenanthrolines has been investigated. A range of chiral [x,y-b]-cycloalkeno-condensed phenanthrolines has been prepared in one step from steroidal or other cyclic ketones from the chiral pool and 8-amino-7-quinolinecarbaldehyde (1) via base-catalyzed condensation. Phenanthroline derivatives are formed in good yields with unhindered ketones, but the reaction proceeds even with sterically congested substrates such as camphor, albeit in low yield. The utility of the Friedl?nder condensation has been extended to the synthesis of chiral 3-alkyl-substituted phenanthrolines from monoalkyl-substituted acetaldehydes.     

Synthesis of chiral allylic phosphonates via asymmetric reductive cross-coupling of α-bromophosphonates and vinyl bromides

Chiral phosphine-containing skeletons play a pivotal role in bioactive natural products, pharmaceuticals, chiral catalysts, and ligands. Despite considerable progress has been made in the synthesis of chiral phosphorus compounds, the development of facile and modular methods to access chiral allylic phosphorus compounds remains challenging due to the simultaneous control required for reactivity, enantioselectivity, and stereoselectivity. Herein, we present a general and modular platform to achie...     

Synthesis of 1,3-benzothiazines by intramolecular dehydrogenative C–S cross-coupling in a flow electrolysis cell

Dehydrogenative cyclization of thioamides is an attractive approach for the synthesis of S-heterocycles. Reported herein is an electrochemical dehydrogenative cyclization reaction of N-benzyl thioamides in a flow electrolysis cell. The continuous-flow electrosynthesis has addressed the limitations associated with previously reported methods for the cyclization of alkylthioamides and provide a transition metal-and oxidizing reagent-free access to various functionalized 1,3-benzothiazines in good yields.     

Titanium-mediated reductive cross-coupling reactions of imines with nitriles: an efficient route for the synthesis of α-aminoketones or 1,2-diketones

The reaction of imines with low-valent titanium species, generated in situ by using Ti(OⁱPr)₄/2 c-C₅H₉MgCl reagent, affords titanium–imine complex, which can couple with nitriles to provide 2,5-diazatitanacyclopentenes. α-Aminoketones are obtained in good yields by quenching the corresponding 2,5-diazatitanacyclopentenes with aqueous HCl solution. However, when the reaction is first quenched with MeOH in air followed by addition of aqueous HCl solution, 1,2-diketones are formed in good to high yields.     

Synthesis of benzannulated spiroacetals using chiral gold–phosphine complexes and chiral anions

The development of an asymmetric gold-catalysed dihydroalkoxylation strategy for the synthesis of the 3′H-spiro[chroman-2,1′-isobenzofuran] spiroacetal ring system 5 is described. Spiroacetal was generated in up to 87:13 enantiomeric ratio using chiral gold–phosphine complexes and chiral silver phosphate Ag(S)-TRIP.     

Application of chiral N,N′-dialkyl-1,2-cyclohexanediamine derivatives in asymmetric copper(II)-catalyzed Henry reactions

A series of chiral N,N′-dialkyl-1,2-cyclohexanediamine derivatives were designed, synthesized, and applied as ligands in asymmetric copper(II)-catalyzed Henry reactions. The catalysts based on such ligands and copper(II) acetate were found to promote asymmetric Henry reactions between aromatic/aliphatic aldehydes and nitromethane efficiently, and could provide the corresponding β-nitroalcohols in very good yields and with enantioselectivities of up to 93.6%.     

Aminoamidines. 5. Synthesis and acetylation of N,N1,N2-triaryl-substituted β-aminoamidines

Triaryl-substituted -aminoamidines were obtained by the reaction of ,-unsaturated N-arylimidoyl chlorides with arylamines. Acylation of the products gave the products from monosubstitution at the -amino group. Triaryl-substituted -aminoamidines react with phosgene and with oxalyl chloride to form 4-aryliminoperhydropyrimidin-2-ones and 5-aryliminoperhydro-1,4-diazepine-2,3-diones, respectively.For previous communication, see [1].A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan' Scientific Center, Russian Academy of Sciences, 420083 Kazan'. Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 11, pp. 2633–2642, November, 1992.     

Asymmetric synthesis of β,β-difluoroamino acids via cross-coupling and Strecker reactions

β,β-Difluoroamino acids were synthesized from commercially available ethyl bromodifluoroacetate using cross-coupling and Strecker reactions as key steps. The coupling reaction of aryl iodides with ethyl bromodifluoroacetate gave the corresponding coupling products, which were transformed to 2-difluoromethyl-1,3-oxazolidines in two steps. Boron trifluoride etherate promoted Strecker reaction of 2-difluoromethyl-1,3-oxazolidines gave α-amino nitriles in good yields and diastereoselectivities. After removal of chiral auxiliary and hydrolysis of the nitrile group, β,β-difluorophenylalanine was obtained with 73% ee. Partial racemization occurred during the hydrolysis of nitrile group.