Preparation of isoindolinones via a palladium-catalyzed diamination

A Pd(II)-catalyzed cyclization using oxidative olefin diamination was developed for the preparation of isoindolinones from ortho-olefinic N-methoxybenzamides. Using the optimized reaction conditions, the desired products were obtained in up to 90% yield using NFSI as the oxidant. This reaction provides an efficient and direct access to isoindolinones with amine functionality, an important drug skeleton.     

The combination of 2-NsNH2/NCS and MeCN as the nitrogen sources for the regio- and stereoselective formation of imidazolines from α,β-unsaturated ketones

A new nitrogen source combination was found for the regio- and stereoselective diamination of α,β-unsaturated ketones. This combination employs the readily available and inexpensive combination of NCS and 2-NsNH₂ as the electrophilic nitrogen source, and acetonitrile as the nucleophilic nitrogen source, respectively. The reaction is easily performed by mixing olefin, 2-NsNH₂, NCS and 4 Å molecular sieves in freshly distilled acetonitrile at room temperature. The reaction is chemoselective without the formation of any haloamine side products. A new aziridinium ion formed from enones and 2-NsNHCl is suggested to exist and to react with nitrile via a [2+3] cycloaddition mechanism, which is responsible for the excellent regio-, stereoselectivity of the resulting diamination products.     

Base and catalyst-free synthesis of nitrobenzodiazepines via a cascade N-nitroallylation-intramolecular aza-Michael addition involving o-phenylenediamines and nitroallylic acetates

A [4+3] annulation of o-phenylenediamines with primary nitroallylic acetates affords nitrobenzodiazepines (NBDZs) in good to excellent yield. The reaction which proceeds in MeOH at room temperature in the absence of any base or catalyst involves a cascade S_N2 N-nitroallylation-intramolecular aza-Michael addition sequence. In the case of mono-N-arylated o-phenylenediamines and o-aminobenzamides, the reaction stops at the S_N2 stage affording nitroallylic amines. On the other hand, reaction of o-aminobenzamides with secondary nitroallylic acetates delivers S_N2′ products. Formation of stable S_N2 and S_N2′ products provides insights into the reactivity of primary and secondary nitroallylic acetates and also the mechanism of formation of nitrobenzodiazepines.     

The reaction of biphenyl radical anion and dianion with alkyl fluorides. From ET to SN2 reaction pathways and synthetic applications

The reaction of dilithium biphenyl (Li₂C₁₂H₁₀) with alkyl fluorides has been studied from the point of view of the distribution of products. Two main reaction pathways, the nucleophilic substitution (S_N2) and the electron transfer (ET), can compete to yield the same alkylation products in what is known as the S_N2-ET dichotomy. S_N2 seems to be the main mechanism operating with primary alkyl fluorides (n-RF). Alkylation proceeds in good yields, and the resulting alkylated dihydrobiphenyl anion (n-RC₁₂H₁₀Li) can be trapped with a second conventional electrophile (E⁺) affording synthetically interesting dearomatized biphenyl derivatives (n-RC₁₂H₁₀E). The reaction gives a higher amount of ET products as we move to secondary (s-RF) and to tertiary alkyl fluorides (t-RF), in which case the mechanism seems to be dominated by ET. In this case, alkylation by radical coupling is still feasible, giving access to the synthesis of t-RC₁₂H₁₀E, although in lower yields. A rational interpretation of this S_N2-ET dichotomy is given on the basis of the full distribution of products observed when 5-hexenyl fluoride and 1,1-dimethyl-5-hexenyl fluoride were are used as radical probes in their reaction with Li₂C₁₂H₁₀ and LiC₁₂H₁₀.     

Potential N‐Heterocyclic Carbene Precursors in the Palladium‐Catalyzed Heck Reaction

A novel 1‐(cyclobutylmethyl)‐substi‐tuted imidazolidinium/benzimidazolium salts as N‐heterocyclic carbene (NHC) precursors were successfully synthesized and characterized by ¹H NMR, ¹³C NMR, IR, and elemental analysis techniques. These compounds were easily prepared from the reaction of N‐alkyl imidazoline/N‐alkyl benzimidazole with bromomethylcyclobutane in high yields. The in situ formed catalytic system derived from the NHC precursor and Pd(OAc)₂ was used in the Heck reaction between aryl halides and styrene with potassium hydroxide in water. The corresponding Heck products were obtained in good yields. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 24:77–83, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21065     

Palladium-catalyzed highly regioselective and stereoselective arylation of electron-rich allylamines with aryl bromides

A palladium-catalyzed, highly efficient Heck arylation of electron-rich N,N-diprotected allylamine derivatives with a wide range of aryl bromides under ligand-free conditions has been developed. In the presence of Pd(OAc)₂ and an appropriate additive, the reaction proceeds with excellent regioselectivity and stereoselectivity, leading exclusively to the γ-arylated (E)-allylamine products in good to excellent yields. It was found that the choice of solvent, olefin, additive and temperature has an important influence on the reaction. Worthy of note is that good results were observed only when using N,N-diprotected allylamines containing carbamate moiety, and the steric properties of allylamines also have important impacts on the regiocontrol. The use of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or HQ (hydroquinone) as the additive is also crucial for securing a faster reaction rate. This method provides a straightforward approach for the efficient synthesis of various γ-arylated, linear (E)-allylamines.     

Copper fluorapatite catalyzed N-arylation of heterocycles with bromo and iodoarenes

Copper exchanged fluorapatite (CuFAP) is an effective heterogeneous catalyst for N-arylation of heterocycles with bromo- or iodoarenes using K₂CO₃ as base. N-Arylated products were isolated in good to excellent yields, demonstrating the versatility of the reaction.     

Reactions of lithiated 2,5-dimethylazaferrocene with selected electrophiles

Lithiation of 2,5-dimethylazaferrocene 1 with sec-BuLi/TMEDA in THF at −78 °C proceeds (as shown by quenching with D₂O) to comparable extent on the methyl groups and the Cp ring. However, the outcome of the reaction of the lithiated 1 with an electrophile depends on the nature of this electrophile. In the reaction with 4-methoxybenzaldehyde only the product originated from the lateral lithiation is formed, whereas the reaction with 4-methoxyacetophenone and 4,4′-dimethoxybenzophenone afforded mixtures of the products resulting from lateral and ring-lithiation. Similar results were also obtained in the reaction of lithiated 1 with chlorodiphenylphosphine and diphenyl diselenide. On the other hand, the exclusive formation of the Cp-substituted product was observed in the reaction of lithiated 1 with N,N-dimethylformamide. The structures of selected products (oily compounds were transformed into the corresponding crystalline W(CO)₅-complexes) were confirmed by X-ray diffraction. The presented reactions open a novel entry to specifically substituted azaferrocenes (especially those containing heteroatom substituents) with potential applications as ligands for the homogenous catalysis.     

Intramolecular diamination and alkoxyamination of alkenes with N-sulfonyl ureas employing N-iodosuccinimide

Reaction of N-δ-alkenyl-N′-sulfonyl urea 1 with N-iodosuccinimde (NIS; 2 equiv) and a catalytic amount of AgOTf (20 mol %) at room temperature led to intramolecular alkoxyamination to form bicyclic isourea 2a in 95% isolated yield. In comparison, reaction of 1 with NIS and sodium bicarbonate (1 equiv) at room temperature led to isolation of bicyclic imidazolidin-2-one 2b in 91% yield. These NIS-mediated alkoxyamination and diamination protocols were effective for a range of N-δ-alkenyl-N′-sulfonyl ureas to form the corresponding heterobicyclic compounds in good yield with high chemoselectivity and good to excellent diastereoselectivity.     

N,N-dichloro-2-nitrobenzenesulfonamide as the electrophilic nitrogen source for direct diamination of enones

N,N-dichloro-o-nitrobenzenesulfonamide (2-NsNCl2) was found to be an effective electrophilic nitrogen source for the direct diamination of alpha,beta-unsaturated ketones without the use of any metal catalysts. The reaction is very convenient to carry out without the protection of inert gases. Molecular sieves (4 A) and temperature were found to play key roles in controlling the formations of 3-trichloromethyl and dichloromethyl imidazoline products (16 examples). The 2-Ns-protection group of the resulting diamine products can be easily cleaved under mild Fukuyama's conditions. A new mechanism hypothesis of [2+3] cyclization and N-chlorination has been proposed to explain the product structures, particularly their regio- and stereochemistry.     

Inorganic base-mediated stereoselective hydroamination of arylalkynes with imidazole: An efficient access to N-vinylimidazoles

A metal-free inorganic base-mediated highly stereoselective hydroamination of arylalkynes with imidazoles has been developed, and the corresponding N-vinylimidazoles were obtained in good yields and with moderate to excellent stereoselectivities (up to 99:1). For the electron rich alkynes, the reaction system of CsOH·H₂O/NMP/140?°C led to the predominant formation of E-addition products, while the reaction system of KOH/NMP/90?°C afforded the Z-isomers as the major product. The electron deficient alkynes furnished predominantly the E-addition products in both reaction systems. This study essentially provides a general and an efficient protocol for the synthesis of E-isomer of the N-vinylimidazoles.     

Convergent syntheses of carbon-13 labeled midazolam and 1′-hydroxymidazolam

For the purpose of drug interaction studies, the stable-isotope labeled [¹³C₃]midazolam and its metabolite, 1′-hydroxy-[¹³C₃]midazolam were synthesized in four and five steps in overall yields of 25.5% and 14.2%, from 7-chloro-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine, respectively, by a convergent synthesis, in which a key imidazoline ring formation was achieved by the facile reaction of [¹³C]2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine with varying ethyl imidate hydrochlorides. The scrambling of C-3 and C-4 labeling in intermediate diamine, and consequently in the final products, as well as the formation of a Δ^4,5 isomer of 1′-hydroxy-[¹³C₃]midazolam was observed and explained.     

Convenient synthesis of chiral tryptophan derivatives using Negishi cross-coupling

A facile synthetic procedure for chiral tryptophan derivatives using Negishi cross-coupling reaction of serine-derived iodoalanine with 3-haloindole is described. The best result was obtained when the reaction of N-tosyl-3-bromoindole with N-Cbz-iodoalanine methyl ester was carried out by the combination of Pd₂(dba)₃ and sterically hindered ferrocenyl ligand Q-PHOS. This reaction condition not only gave the desired tryptophan derivative as high as 76% yield, but also suppressed the formation of undesired products, the dehalogenated indole and the homodimer of indole, which were difficult to separate. This reaction was extended to the synthesis of various tryptophan derivatives having substituents on the benzene ring. The characteristic of this reaction is the practical biomimetic synthesis of chiral tryptophan derivatives in one-step.     

New investigation of Vilsmeier-type reaction using pyrazolones with various amides

New investigation of Vilsmeier-type reaction was evaluated to realize the solvent effect by using pyrazolones to react with various of amides, including formamide, N-methylformamide, N-propylformamide, N-tert-butylformamide, N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), N,N-dipropylformamide (DPF), N,N-diisopropylformamide, N,N-dibutylformamide, piperidine-1-carbaldehyde, and pyrrolidine-1-carbaldehyde, in the presence of phosphorous oxychloride POCl₃. The unexpected resulting products were observed in this work according to the difference chemoseletivities of substituted amides. The plausible reactive pathways were proposed to explain the experimental result.     

Isocyanide based multicomponent reactions of oxazolidines and related systems

N-Alkyloxazolidines react in a multicomponent reaction with carboxylic acids and isocyanides to give N-acyloxyethylamino acid amides. The previously reported reaction conditions were improved using a design of experiments approach (DoE). Under the optimised conditions, good yields of the N-acyloxyethylamino acid amide products are obtained both via a three- or four-component approach from N-alkylethanolamines, aldehydes/ketones, isocyanides and carboxylic acids. The reaction of oxazolidines without a nitrogen substituent was found to give either the expected Ugi products or the N-acyloxyethylamino acid amides depending on the choice of reaction conditions. Optimised reaction conditions were also developed for the ring-expansion of oxazolidines to morpholin-2-ones via reaction with an isocyanide followed by hydrolysis. The mechanistic pathway of the multicomponent reaction was briefly investigated using an ¹⁸O labelling experiment. The carboxylic acid component can be replaced by a range of other acidic nucleophiles including thiobenzoic acid, thiophenol or 5-phenyltetrazole, which are incorporated via an alternative pathway. These latter reactions can also be applied to 2-aminotetrahydrofurans, 2-aminotetrahydropyrans or 4-hydroxybut-2-one, further extending the structural diversity of the multicomponent reaction products.     

Rhodium‐Catalyzed Alkene Difunctionalization with Nitrenes

The Rh^II‐catalyzed oxyamination and diamination of alkenes generate 1,2‐amino alcohols and 1,2‐diamines, respectively, in good to excellent yields and with complete regiocontrol. In the case of diamination, the intramolecular reaction provides an efficient method for the preparation of pyrrolidines, and the intermolecular reaction produces vicinal amines with orthogonal protecting groups. These alkene difunctionalizations proceed by aziridination followed by nucleophilic ring opening induced by an Rh‐bound nitrene generated in situ, details of which were uncovered by both experimental and theoretical studies. In particular, DFT calculations show that the nitrogen atom of the putative [Rh]₂=NR metallanitrene intermediate is electrophilic and support an aziridine activation pathway by N ??? N=[Rh]₂ bond formation, in addition to the N ??? [Rh]₂=NR coordination mode.     

Ultrasound-assisted addition of alcohols to N-acyliminium ions mediated by In(OTf)3 and synthesis of 1,2,3-triazoles

An easy and mild approach using ultrasound-assisted reaction addition of alcohols to N-acyliminium ion mediated by Lewis acid, In(OTf)₃, allowed the synthesis of ether pyrrolidinones; next, the products were converted to 1,2,3-triazoles using click chemistry reaction conditions. The products in both reactions were afforded in moderate to good yields.     

Dialkylzinc additions with a chiral osmaimidazolidine ligand from asymmetric diamination of olefins

A new chiral ligand was prepared in a convenient two-step procedure starting from an asymmetric diamination reaction. Subsequent treatment of the resulting osmaimidazolidine with a phenyl Grignard reagent and titanium tetra(iso-propoxide) furnished a complex that catalyses asymmetric dialkylzinc additions to aromatic aldehydes.     

Facile synthesis of fluorinated α-imino alkynes by the coupling reaction of imidoyl iodides with terminal alkynes

A series of N-arylbromodifluoroacetimidoyl iodides and 1-alkynes were converted into α-imino alkynes by using Pd(Ph₃)₂Cl₂/CuI as the catalyst under mild conditions. The reaction proceeded smoothly to give the coupling products in good to excellent yields.     

The regioselective C5 halogenation of quinolines using sodium halides under transition metal-free conditions

An efficient and mild halogenation of 8-acylaminoquinoline at the C5 position was described. The reaction utilized easily available sodium halides as the halogen sources and proceeded smoothly under transition metal-free conditions. Various 8-aminoquinolines with a number of functional groups were compatible in this reaction to afford the corresponding halogenated products in moderate to good yields. Moreover, the reaction conditions also tolerated the substrates without the 8-aminoquinolyl auxiliary, such as N-phenyl amide and N-naphthyl amide.