Asymmetric reactions of axially chiral amides: use of removable ortho-substituents in radical cyclizations of o-iodoacrylanilides and N-allyl-N-o-iodoacrylamides

Radical cyclizations of enantiomerically enriched o-iodoacrylanilides and N-allyl-o-iodoanilides bearing a removable ortho-substituent such as trimethylsilyl or bromine provide oxindoles and indoles in good yields and with good to excellent levels of chirality transfer from the N-Ar axis to the new stereocenter. Transition state models for the chirality transfer are suggested. Chemoselectivity of the radical cyclization in favor of the iodine in the case of 2-iodo-6-bromo-N-allylacrylamides has been exploited for the synthesis of chiral pyrroloquinolinones by a one-pot sequence of 5-exo and 6-endo cyclizations.     

Efficient iodine catalyzed chemoselective synthesis of aminals—an access to N,N-acetals by the addition of lactams to N-acyl imines

A highly efficient protocol has been developed for the synthesis of aminals from γ-butyrolactam and benzaldehyde using iodine as Lewis acid catalyst. The attack of γ-butyrolactam nucleophile to intermediate N-acyliminium ion was more favorable, when aryl aldehyde bears the electron donating group (EDG). Iodine plays a key role in these reaction transformations. This current mild protocol is environmentally benign and cost-effective method for the synthesis of industrially and pharmaceutically useful scaffolds.     

Me3SiCl-promoted intramolecular cyclization of aromatic compounds tethered with N,O-acetals leading to the facile preparation of 1,4-benzodiazepine skeletons

The Me₃SiCl-promoted intramolecular aminomethylation of a novel type of N,O-acetals, which were prepared via a facile three-step synthesis from N-alkylaniline derivatives and N-alkyl-2-oxazolidinones that leads to the production of pharmaceutically useful 1,4-benzodiazepine skeletons with a variety of functional groups is described. This method was successfully applied to the facile preparation of both tricyclic benzodiazepine derivatives and a 1,4-benzoxazepine derivative via 7-exo-trig cyclization.     

Axially chiral phosphine-oxazoline ligands in silver(I)-catalyzed asymmetric Mannich reaction of N-Boc aldimines with trimethylsiloxyfuran

Axially chiral phosphine-oxazoline ligand L6 was found to be a fairly effective chiral ligand in silver(I)-catalyzed asymmetric Mannich reaction of N-Boc aldimines with trimethylsiloxyfuran to give the corresponding adducts in up to 97% yield, 7:1 dr and 86% ee (major diastereoisomer).     

Michael addition of chiral formaldehyde N,N-dialkylhydrazones to activated cyclic alkenes

The nucleophilic conjugate addition of chiral formaldehyde N,N-dialkylhydrazones 1 to doubly activated cyclic alkenes 2-8 proceeds smoothly to afford the corresponding Michael adducts 14, 16, 18, 20, 22, 24, and 25 in variable yields and selectivities. The reactions take place either spontaneously or in the presence of MgI₂ as a mild Lewis acid depending on the type of substrate. Release of the chiral auxiliary was achieved by transformation of the hydrazone moiety into acetals, dithioacetals or nitriles.     

Enantioselective aldol reactions of trichlorosilyl enol ethers catalyzed by chiral N,N-dioxides and monodentate N-oxides

Chiral N,N^′-dioxides and monodentate N-oxides were employed as catalysts in catalytic, enantioselective aldol reactions of trichlorosilyl enol ethers. The reactions of acyclic enol ethers using N,N^′-dioxides resulted in the anti-adducts from (E)-enol ethers and the syn-adducts from (Z)-enol ethers. The reactions of cyclic (E)-enol ethers using N,N^′-dioxides gave the anti-adducts, whereas monodentate N-oxides predominantly gave the syn-adducts.     

PTSA catalyzed straightforward protocol for the synthesis of 2-(N-acyl)aminobenzimidazoles and 2-(N-acyl)aminobenzothiazoles in PEG

An efficient PTSA catalyzed synthesis of 2-(N-acyl)aminobenzimidazoles and 2-(N-acyl)aminobenzothiazoles has been described using S-ethylated-N-acylthioureas as substrates and polyethylene glycol as solvent.     

Stereoselective synthesis of 2-methylenepyrrolizidines by tandem cyclization of N-propargylaminyl radicals

Tandem cyclization of N-propargylaminyl radicals, generated by N-chlorination of (E)-alk-4-enylamines 2a-d and 2f followed by treatment with tributyltin radical, afforded 2-methylenepyrrolizidines 3a-d and 3f in a highly stereoselective manner. A similar radical cyclization of (Z)-N-propargyl-1-methyl-5-phenylpent-4-enylamine (2e) gave pyrrolizidine 3b having the same stereochemistry as that obtained from the E isomer 2b.     

Retro-Mannich reactions of 3-alkyl-3,4-dihydro-2H-1,3-benz[e]oxazines and the synthesis of axially chiral resorcinarenes

Intermediates involved in the conversion of 3-alkyl-3,4-dihydro-2H-1,3-benz[e]oxazines into 2-N,N-dialkylaminomethylphenol derivatives, using morpholine and other high boiling secondary amines, have been identified and characterised. Additional experiments have established the involvement of o-quinone methide intermediates in the retro-Mannich reactions. Axially chiral resorcinarenes have been prepared by utilising the exchange reactions.     

Oxidative entry to α-oxy N-acyl aminals and hemiaminals: efficient formation of 2-(N-acylaminal) substituted tetrahydropyrans

An efficient new method to synthesize α-oxy N-acyl aminals and hemiaminals in a single step from readily synthesized N-acyl enamines has been developed using PhI(OAc)₂ as the oxidant. The reaction conditions are very mild and the products are obtained in good yields (65-92%). A possible mechanistic pathway is laid out.     

Asymmetric Kumada-Corriu cross-coupling reaction with Pd2(dba)3 and an N-Ar axially chiral mimetic-type ligand catalyst

A catalyst comprised of Pd₂(dba)₃·CHCl₃ and an N-Ar axially chiral mimetic-type ligand, (S)-N-[2-(diphenylphosphanyl)naphthalene-1-yl]-2-(piperidinylmethyl)piperidine, provides good enantioselectivities for the asymmetric Kumada-Corriu cross-coupling reaction of 1-phenylethylmagnesium chloride and E-β-bromostyrene derivatives with which it is more difficult to achieve high enantioselectivity. Furthermore, in the case of styrene derivatives bearing both vinyl and aryl bromide groups, the chemoselective asymmetric cross-coupling reaction of the vinyl bromide group is observed. This N-Ar axially chiral mimetic-type ligand allows easy synthesis of a wide variety of analogues, and starting from the initial ligand, the enantioselectivity of coupling products is improved by modifying the structure in the ligand.     

A complementary method to obtain N-acyl enamides using the Heck reaction: extending the substrate scope for asymmetric hydrogenation

A method to prepare N-acyl enamides is reported that is complementary to the existing protocols. Heck reaction of a variety of aryl trifluoromethanesulfonates with commercially available N-vinylacetamide occurred in a highly regioselective fashion to provide these valuable synthetic intermediates. This method permits the formation of N-acyl enamides containing functionality that would not be tolerated by the existing methods. Asymmetric hydrogenation using [diphosphine RhCOD]BF₄ complexes provided optically active protected amines in up to 99% ee. De-acylation occurs without affecting the amine enantiopurity.     

Iodine-mediated electrophilic cyclization of 2-alkynylbenzaldoximes leading to the formation of iodoisoquinoline N-oxides

Reaction of 2-alkynylbenzaldoximes 1 with 5 equiv of iodine in EtOH at room temperature gives the corresponding iodoisoquinoline N-oxides 2 in good to excellent yields. The cyclization proceeds very smoothly and quickly without any additives such as bases under very mild reaction conditions.     

Synthesis of poly-substituted tetrahydropyridines from Baylis-Hillman adducts modified with N-allylamino group via radical cyclization

An expedient method was developed for the synthesis of 1,4,5,6-tetrahydropyridines by radical cyclization protocol involving consecutive 1,5-hydrogen transfer and double bond isomerization process starting from Baylis-Hillman adducts.     

Asymmetric addition of trimethylsilylcyanide to N-benzylimines catalyzed by recyclable chiral dimeric V(V) salen complex

Chiral dimeric vanadium (V) salen complex (10 mol%) derived from 5,5-Methylene di-[(S,S)-{N-(3-tert-butyl salicylidine)-N′-(3′,5′-di-tert-butyl salicylidene)]-1,2-cyclohexanediamine] with vanadyl suphate followed by auto oxidation was used as efficient catalyst for enantioselective Strecker reaction of N-benzylimines with TMSCN at −30 °C. Excellent yield (92%) of α-aminonitrile and high chiral induction was achieved (ee up to 94%) in case of 2-methoxy substituted N-benzylimines in 10 h. The catalytic system worked well up to four cycles with retention of enantioselectivity.     

Synthesis of N-tosyl-3,3,4-trisubstituted pyrrolidine derivatives starting from the Baylis-Hillman adducts via radical cyclization

N-Tosyl-3,3-disubstituted-4-vinylpyrrolidine derivatives 3a-c were synthesized via radical cyclization from the modified Baylis-Hillman adducts 2. The required starting materials 2a-c were prepared in moderate yields from the Baylis-Hillman adducts in three steps: (i) acetylation of the Baylis-Hillman adducts, (ii) S_N2′ reaction with tosylamide to prepare 1, and (iii) alkylation with 1,4-dibromo-2-butene.     

10b-Substituted hexahydropyrrolo-isoquinolines: studies on diastereoselective formation of a quaternary carbon stereocenter via N-acyliminium ion cyclization

The stereoselective synthesis of hexahydro-pyrroloisoquinolines with a quaternary carbon stereocenter is described. The presented methodology employs the addition of a Grignard reagent to the carbonyl group of imide 1, derived from l-tartaric acid, followed by acetylation and BF₃·Et₂O induced cyclization. The acetylation-cyclization sequence can be run either as a one-pot process, or stepwise in a selected solvents. The crucial step, an acid-catalyzed carbon-carbon bond-forming reaction via an N-acyliminium ion offers high stereoselectivity, which has been shown to be strongly dependent on the size of the R¹ substituents and the reaction conditions, that is, choice of solvent, amount of a Lewis acid, temperature, and concentration of the substrate. Based on the results observed, participation of solvent in the cyclization, via an N-acyliminium cation is proposed.     

Convenient and efficient Suzuki-Miyaura cross-coupling reactions catalyzed by palladium complexes containing N,N,O-tridentate ligands

N,N,O-Tridentate ligands 1-9 were prepared from the condensation of amines with nine aromatic aldehydes or ketones. These ligands are thermally stable and neither air- nor moisture-sensitive. Combination of either 2-methoxy-6-[(pyridine-2-ylmethylimino)-methyl]-phenol, 1 or 2-(benzothiazol-2-yl-hydrazonomethyl)-4,6-di-tert-butyl-phenol, 6 with Pd(OAc)₂ furnished an excellent catalyst precursor for the Suzuki-Miyaura cross-coupling of various aryl bromides with arylboronic acids. The effects of varying solvents, bases, and ligand/palladium ratios on the performance of the coupling reaction were investigated. The molecular structures of both free ligand 1 and its palladium acetate complex 10 were determined by single-crystal X-ray diffraction methods. The DFT studies revealed that the catalytic performance of palladium complexes involving this type of a ligand may differ greatly upon a small variation in its structure.     

Photophysical properties and photoreduction of N-acetyl- and N-benzoylphthalimides

The photophysical properties and photoreduction of N-acetylphthalimide (AcP) and N-benzoylphthalimide (BzP), N-3,4,5-trimethoxybenzoylphthalimide (trimethoxyBzP) and N-4-nitrobenzoylphthalimide (nitroBzP) were studied by steady-state and transient techniques. Radicals and their precursor triplet states were detected by flash photolysis. The triplet state properties of AcP and BzP were characterized. In contrast, no triplet absorption was observed with ns-detection for trimethoxyBzP and nitroBzP. Specific products are formed upon electron transfer from triethylamine to the photoexcited acylphthalimides. In addition, H-atom transfer from 2-propanol or other alcohols to the triplet state takes place. The properties of several radical intermediates involved in photoreduction of the acylphthalimides as well as some structure-function relationships are described.     

Dialkylzinc mediated radical additions to chiral N-enoyloxazolidinones in the presence of benzaldehyde. Mechanistic investigation, structural characterization of the resulting γ-lactones

Diethylzinc was used in the presence of oxygen to mediate radical additions to chiral N-enoyloxazolidinones derived from fumaric acid. The synthesis of sterically crowded trisubstituted γ-lactones was achieved through a multicomponent reaction involving t-butyl iodide and benzaldehyde in addition to the above mentioned reagents. The domino process includes successively: iodine atom transfer, radical addition, homolytic substitution at zinc, aldol condensation, and lactonization. The diastereoselectivity of the reaction and the structural features of the resulting lactones were investigated. A tentative rationalization is discussed. Comparative experiments carried out with diisopropylzinc were performed.