Methyl‐Selective α‐Oxygenation of Tertiary Amines to Formamides by Employing Copper/Moderately Hindered Nitroxyl Radical (DMN‐AZADO or 1‐Me‐AZADO)

Methyl‐selective α‐oxygenation of tertiary amines is a highly attractive approach for synthesizing formamides while preserving the amine substrate skeletons. Therefore, the development of efficient catalysts that can advance regioselective α‐oxygenation at the N‐methyl positions using molecular oxygen (O₂) as the terminal oxidant is an important subject. In this study, we successfully developed a highly regioselective and efficient aerobic methyl‐selective α‐oxygenation of tertiary amines by employing a Cu/nitroxyl radical catalyst system. The use of moderately hindered nitroxyl radicals, such as 1,5‐dimethyl‐9‐azanoradamantane N‐oxyl (DMN‐AZADO) and 1‐methyl‐2‐azaadamanane N‐oxyl (1‐Me‐AZADO), was very important to promote the oxygenation effectively mainly because these N‐oxyls have longer life‐times than less hindered N‐oxyls. Various types of tertiary N‐methylamines were selectively converted to the corresponding formamides. A plausible reaction mechanism is also discussed on the basis of experimental evidence, together with DFT calculations. The high regioselectivity of this catalyst system stems from steric restriction of the amine‐N‐oxyl interactions.     

Highly Efficient Ruthenium‐Catalyzed N‐Formylation of Amines with H2 and CO2

A highly efficient catalyst system based on ruthenium‐pincer‐type complexes has been discovered for N‐formylation of various amines with CO₂ and H₂, thus affording the corresponding formamides with excellent productivity (turnover numbers of up to 1 940 000 in a single batch) and selectivity. Using a simple catalyst recycling protocol, the catalyst was reused for 12 runs in N,N‐dimethylformamide production without significant loss of activity, thus demonstrating the potential for practical utilization of this cost‐effective process. A one‐pot two‐step procedure for hydrogenation of CO₂ to methanol via the intermediacy of formamide formation has also been developed.     

高选择性N-单甲基化芳香胺的合成

本文报道了一种高效专一性合成N-单甲基芳胺的方法。芳胺先与醋酐反应生成乙酰胺,再与碘甲烷在氢化钠作用下反应生成相应的N-甲基乙酰芳胺。在乙二醇中用酸水解高产率得到相应的N-单甲基芳胺。并将该方法用于药物中间体的合成。     

Characterization of N‐Boc/Fmoc/Z‐N′‐formyl‐gem‐diaminoalkyl derivatives using electrospray ionization multi‐stage mass spectrometry

N‐Boc/Fmoc/Z‐N′‐formyl‐gem‐diaminoalkyl derivatives, intermediates particularly useful in the synthesis of partially modified retro‐inverso peptides, have been characterized by both positive and negative ion electrospray ionization (ESI) ion‐trap multi‐stage mass spectrometry (MSⁿ). The MS² collision induced dissociation (CID) spectra of the sodium adduct of the formamides derived from the corresponding N‐Fmoc/Z‐amino acids, dipeptide and tripeptide acids show the [M + Na‐NH₂CHO]⁺ ion, arising from the loss of formamide, as the base peak. Differently, the MS² CID spectra of [M + Na]⁺ ion of all the N‐Boc derivatives yield the abundant [M + Na‐C₄H₈]⁺ and [M + Na‐Boc + H]⁺ ions because of the loss of isobutylene and CO₂ from the Boc protecting function. Useful information on the type of amino acids and their sequence in the N‐protected dipeptidyl and tripeptidyl‐N′‐formamides is provided by MS² and subsequent MSⁿ experiments on the respective precursor ions. The negative ion ESI mass spectra of these oligomers show, in addition to [M‐H]^?, [M + HCOO]^? and [M + Cl]^? ions, the presence of in‐source CID fragment ions deriving from the involvement of the N‐protecting group. Furthermore, MSⁿ spectra of [M + Cl]^? ion of N‐protected dipeptide and tripeptide derivatives show characteristic fragmentations that are useful for determining the nature of the C‐terminal gem‐diamino residue. The present paper represents an initial attempt to study the ESI‐MS behavior of these important intermediates and lays the groundwork for structural‐based studies on more complex partially modified retro‐inverso peptides. Copyright © 2013 John Wiley & Sons, Ltd.     

A Novel Synthesis of Quinazolines by Cyclization of 1‐(2‐Isocyanophenyl)alkylideneamines Generated by the Treatment of 2‐(1‐Azidoalkyl)phenyl Isocyanides with NaH

A new and efficient method for the synthesis of quinazolines has been developed. Thus, N‐[2‐(1‐azidoalkyl)phenyl]formamides 1 are dehydrated with POCl₃ to give the corresponding 2‐(1‐azidoalkyl)phenyl isocyanides 2 , which are then treated with NaH in DMF at 0° to give quinazolines 6 in satisfactory yields via cyclization of 1‐(2‐isocyanophenyl)alkylideneamine intermediates 4 . This methodology can be applied to the synthesis of the 7‐azaanalogs of quinazolines, i.e., pyrido[3,4‐d]pyrimidines 9 .     

Accelerating effects of N‐aryl‐N′,N′‐dialkyl ureas on epoxy‐dicyandiamide curing system

This report focuses on epoxy‐dicyandiamide (DICY) curing system accelerated by N‐aryl‐N′,N′‐dialkyl urea, aiming at clarifying the accelerating mechanism and the relationship between accelerating effect and molecular structure of the accelerators. Nine N‐aryl‐N′,N′‐dialkyl ureas were synthesized and investigated with measurements of differential scanning calorimetry, thermo gravimetric/differential thermal analysis and NMR spectroscopy. The results revealed that the ureas released the corresponding secondary amines by the thermal dissociation in the presence of epoxide, which led to the formation of tertiary amines that catalyze the addition reaction of DICY to epoxide. Moreover, a tendency that the ureas able to release more compact amines exhibited higher acceleration effects was discovered. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Ring Opening of N‐Sulfonyl Aziridines by Amines in Silica‐Water

Ring opening reactions of N‐sulfonyl aziridines by primary and secondary amines in silica gel (SG)‐water system were achieved, which provided a mild, practical and environmentally benign method to synthesize mono‐ and bis‐sulfonyl substituted amines. When primary and secondary amines were used in excess, they reacted with N‐sulfonyl aziridines smoothly at room temperature, mainly affording 1:1 ring opening products. Reactions of primary amines with 2 equiv. of aziridines produced 2:1 ring opening products. Some 1:1 products can be cyclized with CS₂ to synthesize N‐sulfonyl cyclothioureas also in water.     

Microwave‐Assisted Synthesis of Novel 2,4‐Dihydro‐5‐[4‐(trifluoromethyl)phenyl]‐3H‐1,2,4‐triazol‐3‐ones and Potentiometric Determination of Their pKa in Nonaqueous Solvents

The novel 4‐amino‐ or 4‐aryl‐substituted 2,4‐dihydro‐5‐[(4‐trifluoromethyl)phenyl]‐3H‐1,2,4‐triazol‐3‐ones 3a – 3g were synthesized by reaction of N‐(ethoxycarbonyl)‐4‐(trifluoromethyl)benzenehydrazonic acid ethyl ester ( 2 ) and primary amines or hydrazine by microwave irradiation. Compounds 3a – 3g were potentiometrically titrated with tetrabutylammonium hydroxide (Bu₄NOH) in four nonaqueous solvents, i.e., ⁱPrOH, ^tBuOH, MeCN, and N,N‐dimethylformamide (DMF). Also half‐neutralization potential values and the corresponding pK_a values were determined in all cases.     

One‐Pot Synthesis of N,N‐Disubstituted (Z)‐4‐(Halomethylidene)‐4H‐3,1‐benzothiazin‐2‐amines from 2‐(2,2‐Dihaloethenyl)phenyl Isothiocyanates and Secondary Amines

We have developed a one‐pot procedure for the preparation of N,N‐disubstituted (Z)‐4‐(halomethylidene)‐4H‐3,1‐benzothiazin‐2‐amines 3 from 2‐(2,2‐dihaloethenyl)phenyl isothiocyanates 1 , easily accessible from known 2‐(2,2‐dihaloethenyl)benzenamines by a three‐step sequence, and secondary amines. Thus, the isothiocyanates 1 react with secondary amines to afford the corresponding thiourea derivatives, of which the treatment with NaH provides the desired products.     

2,2,2‐Trifluoroacetophenone as an Organocatalyst for the Oxidation of Tertiary Amines and Azines to N‐Oxides

A cheap, mild and environmentally friendly oxidation of tertiary amines and azines to the corresponding N‐oxides is reported by using polyfluoroalkyl ketones as efficient organocatalysts. 2,2,2‐Trifluoroacetophenone was identified as the optimum catalyst for the oxidation of aliphatic tertiary amines and azines. This oxidation is chemoselective and proceeds in high‐to‐quantitative yields utilizing 10 mol % of the catalyst and H₂O₂ as the oxidant.     

Synthesis of 3‐Fluoropyrrolidines and 4‐Fluoropyrrolidin‐2‐ones from Allylic Fluorides

Various 3‐fluoropyrrolidines and 4‐fluoropyrrolidin‐2‐ones were prepared by 5‐exo‐trig iodocyclisation from allylic fluorides bearing a pending nitrogen nucleophile. These bench‐stable precursors were made accessible upon electrophilic fluorination of the corresponding allylsilanes. The presence of the allylic fluorine substituent induces syn‐stereocontrol upon iodocyclisation with diastereomeric ratios ranging from 10:1 to > 20:1 for all N‐tosyl‐3‐fluoropent‐4‐en‐1‐amines and amides. The sense and level of stereocontrol is strikingly similar to the corresponding iodocyclisation of structurally related allylic fluorides bearing pending oxygen nucleophiles. These results suggest that the syn selectivity observed upon ring closure involves I₂–π complexes with the fluorine positioned inside.     

Novel Asymmetric Formylation of Aromatic Compounds: Enantioselective Synthesis of Formyl 7,8‐Dipropyltetrathia[7]helicenes

Asymmetric formylation of aromatic compounds is virtually unexplored. We report the synthesis and evaluation of a library including 20 new chiral formamides in the kinetic resolution of 7,8‐dipropyltetrathia[7]helicene, affording the corresponding formyl‐ or diformylhelicenes in up to 73 % ee, making enantiopure compounds available by recrystallisation. With the N,N‐disubstituted formamides used in this study, the best enantioselectivity has been achieved with R¹=iPr, R²=Me, R³=H, R⁴=1‐naphthyl or its 1‐pyrenyl equivalent.     

Synthesis and tuberculostatic activity of novel N′‐methyl‐4‐(pyrrolidin‐1‐yl)picolinohydrazide and N′‐methylpyrimidine‐2‐carbohydrazide derivatives

The synthesis of N′‐methyl‐4‐(pyrrolidin‐1‐yl)picolinohydrazide and N′‐methyl‐pyrimidine‐2‐carbohydrazide derivatives ( 5a and 5b ) was carried out. These compounds were used as starting materials to obtain methyl N′‐methylhydrazinecarbodithioates 6a and 6b , which, on reaction with either triethylamine or hydrazine, gave corresponding 1,3,4‐oxadiazioles 7a and 7b or 1,2,4‐triazoles 9a and 9b with the free NH₂ group at the N‐4 position, respectively. Compounds 8a – e , particularly containing cyclic amines at N‐4 of the 1,2,4‐triazole ring, were also obtained. Synthesized compounds were tested in vitro for their activity against Mycobacterium tuberculosis. The structure–activity relationship analysis for obtained compounds was done. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:223–230, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21008     

Synthesis of homoallylic amines and acylhydrazides by tin powder‐promoted multicomponent one‐pot allylation reactions

An efficient process for the synthesis of homoallylic amines and N′‐homoallylic hydrazides is developed from the one‐pot reaction of carbonyl compounds, amines or N‐acylhydrazines, allyllic bromide and tin powder using water as solvent. N‐Acylhydrazines are found to be more reactive than amines in these processes. They can react not only with aldehydes but also with ketones to give the corresponding N′‐homoallylic hydrazides. Copyright © 2016 John Wiley & Sons, Ltd.     

Regio‐ and Enantioselective Synthesis of N‐Allylindoles by Iridium‐Catalyzed Allylic Amination/Transition‐Metal‐Catalyzed Cyclization Reactions

Regio‐ and enantioselective synthesis of N‐allylindoles was realized through an iridium‐catalyzed asymmetric allylic amination reaction with 2‐alkynylanilines and subsequent transition‐metal‐catalyzed cyclization reactions. The highly enantioenriched allylic amines prepared from Ir‐catalysis were treated with catalytic amount of NaAuCl₄ ? 2 H₂O or PdCl₂ providing various substituted N‐allylindoles in excellent yields and enantioselectivities.     

A Convenient and Facile Hantzsch Synthesis of Aryl Imidazo[1,2‐b]Isoxazolyl‐N‐aryl Thiazol Amines

The Hantzsch synthesis of novel aryl imidazo[1,2‐b]isoxazolyl‐N‐aryl thiazol amines 5 analogues were described. Reaction of 3‐aminoisoxazole 1 with substituted phenacyl bromides 2 in dry ethanol afforded the corresponding 6‐methyl‐3‐arylimidazo[1,2‐b]isoxazoles 3 in good yields. Compounds 3 on reaction with chloroacetyl chloride in 1,4‐dioxane furnished the corresponding 2‐chloro‐1‐(6‐methyl‐3‐arylimidazo[1,2‐b]isoxazol‐2‐yl)ethanones 4 . Compounds 4 on heating with N‐aryl thioureas in an oil bath underwent cyclization to afford the title compounds viz., imidazo[1,2‐b]isoxazolyl‐N‐aryl thiazol amines 5 in moderate to good yields by Hantzsch synthesis.     

Disulfonimide‐Catalyzed Asymmetric Reduction of N‐Alkyl Imines

A chiral disulfonimide (DSI)‐catalyzed asymmetric reduction of N‐alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc₂O has been developed. The reaction delivers Boc‐protected N‐alkyl amines with excellent yields and enantioselectivity. The method tolerates a large variety of alkyl amines, thus illustrating potential for a general reductive cross‐coupling of ketones with diverse amines, and it was applied in the synthesis of the pharmaceuticals (S)‐Rivastigmine, NPS R‐568 Hydrochloride, and (R)‐Fendiline.     

Manganese‐Catalyzed N‐Formylation of Amines by Methanol Liberating H2: A Catalytic and Mechanistic Study

The first example of a base metal (manganese) catalyzed acceptorless dehydrogenative coupling of methanol and amines to form formamides is reported herein. The novel pincer complex (i Pr‐PN^HP)Mn(H)(CO)₂ catalyzes the reaction under mild conditions in the absence of any additives, bases, or hydrogen acceptors. Mechanistic insight based on the observation of an intermediate and DFT calculations is also provided.     

Ligand‐Controlled α‐ and β‐Arylation of Acyclic N‐Boc Amines

The palladium‐catalyzed ligand‐controlled arylation of α‐zincated acyclic amines, obtained by directed α‐lithiation and transmetalation, is described. Whereas PtBu₃ gave rise to α‐arylated Boc‐protected amines, more flexible N‐phenylazole‐based phosphine ligands induced major β‐arylation through migrative cross‐coupling.     

Highly Efficient One-Pot Synthesis of 2-Arylmethyl N-Substituted Anilines via Yb（OTf）3 Catalyzed Three-Component Reaction

An efficient method has been developed for one-pot three-component coupling reactions of various aldehydes, 1-cyclohexen-2-one, and primary or secondary amines in the presence of a catalytic amount of Yb（OTf）3 under mild conditions to afford the corresponding 2-arylmethyl N-substituted anilines in good yields. In addition, the catalyst was easily recovered and could be reused for at least four cycles without any loss of activity.