Redox‐Neutral α,β‐Difunctionalization of Cyclic Amines

In contrast to the continuously growing number of methods that allow for the efficient α‐functionalization of amines, few strategies exist that enable the direct functionalization of amines in the β‐position. A general redox‐neutral strategy is outlined for amine β‐functionalization and α,β‐difunctionalization that utilizes enamines generated in situ. This concept is demonstrated in the context of preparing polycyclic N,O‐acetals from simple 1‐(aminomethyl)‐β‐naphthols and 2‐(aminomethyl)‐phenols.     

Analysis of short‐chain aliphatic amines in food and water samples using a near infrared cyanine 1‐(ε‐succinimydyl‐hexanoate)‐1′‐methyl‐3,3,3′,3′‐tetramethyl‐indocarbocyanine‐5,5′‐disulfonate potassium with CE–LIF detection

Precolumn derivatization of six short‐chain aliphatic amines by a near‐infrared dye, 1‐(ε‐succinimydyl‐hexanoate)‐1′‐methyl‐3,3,3′,3′‐tetramethyl‐indocarbocyanine‐5,5′‐ disulfonate potassium (MeCy5‐OSu), followed by MEKC–CE–LIF detection has been developed as a method for the determination of aliphatic amines in environmental water and food. Optimum derivatization was operated nicely in pH 9.0 borate buffer at 20°C for 30 min. Well separated peaks were observed with a pH 9.5 BGE containing 10 mmol L^?1 phosphoric acid, 20 mmol L^?1 SDS, and 7% methanol buffered with 1.0 mol L^?1 NaOH. The separation procedure was rapidly achieved within 11 min and the matrix interferences could be effectively eliminated. A linear calibration graph was obtained for 5–200 nmol L^?1 analytes with a correlation coefficient in the range 0.9933–0.9995 for amines. This method was successfully utilized to determine aliphatic amines in lake, sewage water, and red wine with recoveries ranging from 96.4 to 105% and the RSDs ranging from 0.9 to 2.9%. Near‐infrared, LIF‐detector‐compatible MeCy5‐OSu was proved suitable for the accurate, sensitive, and rapid separation and determination of aliphatic amines in water and food samples.     

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.     

2,4‐Dinitrophenol‐Catalyzed α‐C(sp3)−H and C(sp)−H Bond Functionalization of Cyclic Amines and Alkynes: Highly Regio‐/Diastereoselective Synthesis of α‐Alkynyl‐3‐Amino‐2‐Oxindoles

A transition‐metal‐ and oxidant‐free DNP (2,4‐dinitrophenol)‐catalyzed atom‐economical regio‐ and diastereoselective synthesis of monofunctionalized α‐alkynyl‐3‐amino‐2‐oxindole derivatives by C?H bond functionalization of cyclic amines and alkynes with indoline‐2,3‐diones has been developed. This cascade event sequentially involves the reductive amination of indoline‐2,3‐dione by imine formation and cross coupling between C(sp³)?H and C(sp)?H of the cyclic amines and alkynes. This reaction offers an efficient and attractive pathway to different types of α‐alkynyl‐3‐amino‐2‐oxindole derivatives in good yields with a wide tolerance of functional groups. The salient feature of this methodology is that it completely suppresses the homocoupling of alkynes. To the best of our knowledge, this is the first example of a DNP‐catalyzed metal‐free direct C(sp³)?H and C(sp)?H bond functionalization providing biologically active α‐alkynyl‐3‐amino‐2‐oxindole scaffolds.     

Highly Enantioselective Aza‐Michael Reaction between Alkyl Amines and β‐Trifluoromethyl β‐Aryl Nitroolefins

The aza‐Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza‐Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N‐heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza‐Michael reaction between primary alkyl amines and β‐trifluoromethyl β‐aryl nitroolefins. In contrast to classical conjugate‐addition reactions, a strategy of HOMO‐raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).     

Regioselective Insertion of o‐Carborynes into the α‐CH Bond of Tertiary Amines: Synthesis of α‐Carboranylated Amines

o‐Carboryne can undergo α‐C? H bond insertion with tertiary amines, thus affording α‐carboranylated amines in very good regioselectivity and isolated yields. In this process, the nucleophilic addition of tertiary amines to the multiple bond of o‐carboryne generates a zwitterionic intermediate. An intramolecular proton transfer, followed by a nucleophilic attack leads to the formation of the final product. Thus, regioselectivity is highly dependent upon the acidity of α‐C? H proton of tertiary amines. This approach serves as an efficient methodology for the preparation of a series of 1‐aminoalkyl‐o‐carboranes.     

Two‐Step Synthesis of Multifunctional γ‐Lactams from γ‐Lactone

We present herein an efficient and rapid method for the synthesis of N,1‐dialkyl‐4‐(2‐hydroxyethyl)‐5‐oxopyrrolidine‐3‐carboxamides based on the conversion of γ‐lactone to γ‐lactam via the conjugate addition of primary amines to an ethyl α‐functionalized acrylate followed by intramolecular cyclization.     

Photoredox‐Catalyzed Site‐Selective α‐C(sp3)−H Alkylation of Primary Amine Derivatives

The synthetic utility of tertiary amines to oxidatively generate α‐amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site‐selective α‐functionalization of primary amine derivatives through the generation of α‐amino radical intermediates. Employing visible‐light photoredox catalysis, primary sulfonamides are coupled with electron‐deficient alkenes to efficiently and mildly construct C?C bonds. Interestingly, a divergence between intermolecular hydrogen‐atom transfer (HAT) catalysis and intramolecular [1,5] HAT was observed through precise manipulation of the protecting group. This dichotomy was leveraged to achieve excellent α/δ site‐selectivity.     

Regioselective Insertion of o‐Carborynes into the α‐C?H Bond of Tertiary Amines: Synthesis of α‐Carboranylated Amines

o‐Carboryne can undergo α‐C H bond insertion with tertiary amines, thus affording α‐carboranylated amines in very good regioselectivity and isolated yields. In this process, the nucleophilic addition of tertiary amines to the multiple bond of o‐carboryne generates a zwitterionic intermediate. An intramolecular proton transfer, followed by a nucleophilic attack leads to the formation of the final product. Thus, regioselectivity is highly dependent upon the acidity of α‐C H proton of tertiary amines. This approach serves as an efficient methodology for the preparation of a series of 1‐aminoalkyl‐o‐carboranes.     

Progress in Convergent Paired Electrolysis

Convergent paired electrolysis combines both anodic and cathodic reactions simultaneously in an electrochemical transformation. It provides a highly energy-efficient and divergent approach to conventionally challenging and useful structures. However, the physical separation of the two half-electrode reactions makes it extremely difficult to couple the intermediates arising from the two electrodes. In this concept article, four strategies used in convergent paired electrolysis will be discussed from the perspective of the reaction mechanism: a) metal-catalyzed convergent paired electrolysis, b) convergent paired electrolysis enabled by persistent radical effects, c) microfluidic chemistry applied to convergent paired electrolysis, and d) alternating current electrolysis.     

Synthesis of Nitrogen‐Containing Derivatives of (18α,19β)‐19‐Hydroxy‐2,3‐secooleanane‐2,3,28‐trioic Acid 28,19‐Lactone

The object of this study is the interaction of the cyclic anhydride 2 of (18α,19β)‐19‐hydroxy‐2,3‐secooleanane‐2,3,28‐trioic acid 28,19‐lactone ( 1 ) with primary and secondary amines. It was shown that the products of steric control (the corresponding 2‐amino‐2‐oxo‐3‐oic acids=2‐amides) were formed solely upon the opening of the anhydride cycle by secondary amines (Scheme 2), whereas the interaction with primary amines yielded a mixture of isomeric amides (Scheme 10). In the latter case, the solvent provided a noticeable effect on the reaction selectivity, which was demonstrated in the case of 4‐methoxybenzylamine. The interaction between the resulting 3‐amides and oxalyl chloride yielded the corresponding cyclic imides, whereas under these conditions, 2‐amides formed spiropyrrolidinetriones (Scheme 4).     

1‐Methyl‐3‐phenyl‐3‐thiocyanato‐1H,3H‐quinoline‐2,4‐dione: A novel thiocyanating agent

Under mild reaction conditions, the thiocyanato group is selectively transferred from 1‐methyl‐3‐phenyl‐3‐thiocyanato‐1H,3H‐quinoline‐2,4‐dione ( 3 ) to some nucleophiles. Aliphatic primary and secondary amines are converted to S‐cyanothiohydroxylamines, anilines afford p‐thiocyanatoanilines, Wittig reagent is thiocyanated in α‐position, and thiols are oxidized to disulfides.     

Facile approach to polyurea/malonamide dendrons via a selective ring‐opening addition reaction of azetidine‐2,4‐dione

A bifunctional compound [(4‐isocyanato‐4′(3,3‐dimethyl ‐2,4‐dioxo‐acetidino)diphenylmethane] (MIA) has been used as a building block for the synthesis of novel polyurea/malonamide dendrons. This is based on selectively sequential addition reactions of amines to isocyanato‐azetidine‐2,4‐diones. After incorporation of the MIA onto the growing dendrons, rapid entry into polyurea/malonamide dendrons was achieved via a convergent route with the processing advantages of easy purification, high yield, and rapid synthesis. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 682–688, 2005     

Synthesis α‐aminonitrile through anodic cyanation of N‐benzylpiperidine

Six‐membered cyclic α‐aminonitrile has been prepared from anodic cyanation of N‐benzylpiperidine. Good yields of α‐aminonitriles could be obtained through potentiostatic electrolysis under different conditions. The results also explain why high yield α‐aminonitriles could not be obtained under constant current electrolysis.     

Copper‐Catalyzed Oxidative Dimerizations of 3‐N‐Hydroxy‐aminoprop‐1‐enes to form 1,4‐Dihydroxy‐2,3‐diaminocyclohexanes with C2 Symmetry

This work describes the one‐step construction of complex and important molecular frameworks through copper‐catalyzed oxidations of cheap tertiary amines. Copper‐catalyzed aerobic oxidations of N‐hydroxyaminopropenes to form C₂‐symmetric N‐ and O‐functionalized cyclohexanes are described. Such catalytic oxidations proceed with remarkable stereocontrol and high efficiency. Reductive cleavage of the two N? O bonds of these products delivers 1,4‐dihydroxy‐2,3‐diaminocyclohexanes, which are important skeletons of several bioactive molecules.     

A pitfall of using 2‐[(2E)‐3‐(4‐tert‐butylphenyl)‐2‐methylprop‐2‐enylidene]malononitrile as a matrix in MALDI TOF MS: chemical adduction of matrix to analyte amino groups

2‐[(2E)‐3‐(4‐tert‐Butylphenyl)‐2‐methylprop‐2‐enylidene]malononitrile (DCTB) has been considered as an excellent matrix for matrix‐assisted laser desorption/ionization (MALDI) of many types of synthetic compounds. However, it might provide troublesome results for compounds containing aliphatic primary or secondary amino groups. For these compounds, strong extra ion peaks with a mass difference of 184.1 Da were usually observed, which might falsely indicate the presence of some unknown impurities that were not detected by other matrices. On the basis of the possible mechanisms proposed, these extra ions are the products of nucleophilic reactions between analyte amino groups and DCTB molecules or radical cations. In these reactions, an amino group replaces the dicyanomethylene group of DCTB forming a matrix adduct via a ? C?N‐bond. An aliphatic primary amine could react easily with DCTB and the reaction could start once they are mixed in a MALDI solution. For an aliphatic secondary amine, on the other hand, the reaction most likely occurs in the gas phase. Protonation of amino groups by adding acid seems to be a useful way to stop DCTB adduction for compounds with one single amino group, but not for compounds with multiple amino groups. Unlike aliphatic primary or secondary amines, aliphatic tertiary amines and aromatic amines do not yield DCTB adducts. This is because tertiary amines do not have the required transferrable H‐(N) atom to form an extra ? C?N‐bond, while aromatic amines are not sufficiently nucleophilic to attack DCTB. In view of the possible matrix adduction, care should be taken in MALDI time‐of‐flight mass spectrometry (TOF MS) when DCTB is used as the matrix for compounds containing amino group(s). Copyright © 2010 John Wiley & Sons, Ltd.     

Syntheses of N‐[3‐(1‐methyl‐1H‐2‐imidazolyl)propyl]benzamides and N‐[3‐(1‐methyl‐1H‐2‐imidazolyl)propyl]benzenesulfonamides

A series of substituted N‐(4‐substituted‐benzoyl)‐N‐[3‐(1‐methyl‐1H‐imidazol‐2‐yl)propyl]amines ( 13 ) and N‐arylsulfonyl‐N‐[3‐(1‐methyl‐1H‐imidazol‐2‐yl)propyl]amines ( 14 ) were prepared from the reaction of 3‐(1‐methyl‐1H‐imidazol‐2‐yl)propan‐1‐amine ( 7 ) with substituted benzoyl chloride or substituted‐benzene sulfonyl chloride respectively. Compound 7 was prepared by two independent methods.     

Copper‐Catalyzed Synthesis of γ‐Amino Acids Featuring Quaternary Stereocenters

The first general asymmetric synthesis of γ,γ‐disubstituted γ‐amino acids by copper‐catalyzed ring opening of nonstrained lactones with amines is reported. This approach features ample scope, operational simplicity, and wide functional‐group diversity. The catalytic process allows access to a series of highly functionalized enantioenriched γ‐amino acids featuring quaternary stereocenters with excellent enantiomeric ratios of up to 98:2 and excellent yields of up to 98 %.     

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.     

Synthesis and Reactivity of 5‐Bromopenta‐2,4‐diynenitrile (BrC5N): an Access to π‐Conjugated Scaffolds

The synthesis of 5‐bromopenta‐2,4‐diynenitrile (BrC₅N) in three steps from commercially available compounds is reported. Reacting 5‐bromopenta‐2,4‐diynenitrile with secondary amines led to the formation of stable butadiynamines or enynenitriles, depending on the nature of the amine reactant. The reaction of 5‐bromopenta‐2,4‐diynenitrile with simple terminal alkynes in the presence of secondary amines, copper, and palladium catalysts, provided a straightforward access to original polyfunctional carbon‐rich scaffolds. In this work, different alkynes and secondary amines were tested, which allowed for the preparation of a family of substituted dienes. Given the high synthetic potential of 5‐bromopenta‐2,4‐diynenitrile, we also prepared iodinated counterparts of this compound, that is, 5‐iodopenta‐2,4‐diynenitrile and its lower homologue 3‐iodopropiolonitrile. The UV‐visible spectrum of some relevant compounds was also recorded.