N-(Benzoyloxy)amines: an investigation of their thermal stability, synthesis, and incorporation into novel peptide constructs

A series of N-benzoyloxyamines were pyrolyzed and their decomposition temperatures correlated well with the amine architecture's ability to stabilize a N-centered radical. A variety of amine substrates were treated with a biphasic mixture of benzoyl peroxide (BPO), CH₂Cl₂ and an aqueous carbonate buffer (at pH 10.5). Primary and secondary amines were successfully N-benzoyloxylated in good yield. Tertiary amines and BPO gave low yields of the corresponding N-oxide and complex product mixtures, presumably via radical decomposition. Electron deficient amines (such as fluorinated aliphatic amines, α-aminoacids, α-aminoesters, and α-aminoamides) were not N-benzoyloxylated under these conditions. Instead, N-benzoylation was observed with the fluorinated amines and the reaction was sensitive to temperature and the pH of the aqueous medium. A one-pot-two-step synthesis of N^α-FMOC-l-Leu-N^β-(benzoyloxy)-β-alanine ethyl ester, a peptide containing both an α- and a novel β-amino acid framework, was also developed.     

Synthesis of Poly(glutamic acid-co-aspartic acid) via Combination of N-carboxyanhydride Ring Opening Polymerization with Debenzylation简

The random copolymers of glutamic acid （LG） and aspartic acid （ASP）, poly（LG-co-ASP）, with designed compositions could be successfully synthesized via combination of N-carboxyanhydride ring opening copolymerization with debenzylation. Ring opening copolymerizations of y：benzyl-L-glutamate N-carboxyanhydride （BLG-NCA） and β-benzyl-Laspartate N-carboxyanhydride （BLA-NCA） were carried out by using different amines including triethylamine （TEA）, diethylamine, n-hexylamine （NHA）, triphenylamine, diphenylamine or aniline as initiators. All the 6 amines were highly efficient to get well-defined poly（BLG-co-BLA） copolymers with designed compositions although the polymerizations proceeded via different mechanisms （normal amine mechanism or/and activated monomer mechanism）, which are based on chemical structure of amines. The molecular weights of poly（BLG-co-BLA） copolymers could be mediated by both TEA concentration and polymerization time. Then, debenzylation ofpoly（BLG-co-BLA） copolymers was conducted to prepare the corresponding hydrophilic random eopolymers of poly（LG-co-ASP） with a-subunit structure in ASP structural units. The contents of LG structural units in poly（LG-co-ASP） copolymers matched with those of BLG-NCA in NCA-monomer feeds in ring opening copolymerizations initiated by NHA or TEA and were closed to the theoretical line. The diblock copolymer of poly（BLG-b-BLA） could also be synthesized via living NCA ring opening copolymerization by sequential addition of BLG- NCA and BLA-NCA.     

Synthetic transformations of higher terpenoids: XIV. Synthesis of pyrrololabdanoids from lambertianic acid

Treatment of lambertianic acid methyl ester with lead tetraacetate gave terpenoid 2,5-diacetoxydihydrofuran which reacted with primary amines to yield 3-terpenyl-substituted pyrrol-2(5H)-ones; the reaction with hydrazine led to the corresponding pyridazine derivative. The obtained furanoterpenoids underwent oxidative methoxylation by the action of N-chlorobenzenesulfonamide or N-bromosuccinimide in methanol. 2,5-Dimethoxydihydrofurans thus formed were smoothly converted into 3-substituted furan-2(5H)-one in acid medium. Hydrogenation of 2,5-dimethoxydihydrofurans, followed by treatment with amines, gave 1,3-disubstituted pyrroles.     

Effect of a carboxyl group on the chemiluminescent reaction of tris(2,2′-bipyridine)ruthenium(III) with aliphatic amines

The effect of a carboxyl group beside nitrogen of aliphatic amines on the tris(2,2′-bipyridine)ruthenium(III), Ru(bpy)₃³⁺, chemiluminescent reaction was examined. It has been shown that a carboxylate anion promotes the chemiluminescent reaction at a lower pH and then the aliphatic amines with this substituent can be sensitively detected compared with corresponding aliphatic amines without this substituent. Based on this finding, preliminary studies on simultaneous determination of 4-hydroxyproline, N-methylglycine, N-methylalanine, proline, and pipecolic acid in human serum have been performed using isocratic reversed-phase ion-pair high-performance liquid chromatography (HPLC) with electrogenerated Ru(bpy)₃³⁺ chemiluminescent detection. The detection limits (signal-to-noise ratio of 3) with the proposed method were 3.0, 12, 2.7, 4.6, and 10 nM for 4-hydroxyproline, N-methylglycine, N-methylalanine, proline, and pipecolic acid, respectively.     

A convenient method for the synthesis of N-hydroxyureas

Treatment of amines with 1-(4-nitrophenol)-N-(O-benzylhydroxy)carbamate yields the O-benzyl protected N-hydroxyureas. Hydrogenation of the O-benzyl protected N-hydroxyureas over 5% Pd/BaSO₄ cleanly gives the N-hydroxyureas in good yield. In addition to primary and secondary aliphatic and aromatic amines, this method converts amino sugars to the corresponding N-hydroxyureas without extensive protecting group chemistry.     

Preparation of trifluoromethylated ynamines and their reactions with some electrophilic reagents

N,N-Dialkyl(3,3,3-trifluoro-1-propynyl)amines were prepared by a three-step procedure starting from commercially available 2,2,3,3,3-pentafluoropropanol. The reactions of these trifluoromethylated ynamines with some electrophiles, such as aldehydes, halogens or N-halosuccinimides (NXS), were investigated. The fluorinated ynamines reacted with aldehydes in the presence of a catalytic amount of Lewis acid to provide the corresponding α-(trifluoromethyl)-α,β-unsaturated amides in good to excellent yields with high Z-stereoselectivity. These ynamines reacted with molecular bomine to give, after treatment with sodium hydrogen carbonate, N,N-dialkyl-2-bromo-3,3,3-trifluoropropanamides in good yields. The reaction with an equimolecular amount of NXS in aqueous acetonitrile also gave the corresponding 2-halo-3,3,3-trifluoropropanamides in good to excellent yields. On the other hand, the reaction of the ynamine with NXS in anhydrous acetonitrile led to the formation of the addition products in high yields. Upon treating the addition products with an equimolecular amount of NX′S in aqueous acetonitrile, the corresponding 2,2-dihalo(X,X′)-3,3,3-trifluoropropanamides were produced in nearly quantitative yields.     

An easy three step synthesis of perfluoroalkylated amphetamines

A general synthesis of perfluoroalkylated amphetamines is presented. Initially, 1-aryl-1-iodo-2-(perfluoroalkyl)ethylenes are prepared by radical addition of perfluoroalkyl iodides to arylacetylenes. Key step of the reaction sequence is the following dehydroiodination in the presence of n-BuLi to give 1-perfluoroalkyl-2-arylacetylenes in situ, which are reacted with secondary amines to produce perfluoroalkylated enamines in a new one pot procedure. Final hydrogenation yields the desired products in good yields. By using N,N-dibenzylamine or N-benzylamines the corresponding primary and secondary perfluoroalkylated amines are easily available.     

Synthesis of pyranosyl amidoximes by addition of amines to pyranosyl nitrile oxides

Addition of amines to pyranosyl nitrile oxides, generated by base-induced dehydrochlorination of the corresponding hydroximoyl chloride, affords pyranosyl N-alkyl/aryl-formamide oximes (41-90%). Reaction with amino acid esters yields the corresponding amidoximes and/or 3-pyranosyl-1,2,4-oxadiazin-6-ones. The structure of N-phenyl-C-(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)formamide oxime was established by X-ray crystallography.     

Catalytic guanylation of aliphatic,aromatic, heterocyclic primary and secondary amines using nanocrystalline zinc(II) oxide

Nanocrystalline ZnO was found to be a highly efficient heterogeneous catalyst for the guanylation of amines with various carbodiimides to afford N,N′,N″-trisubstituted guanidines in excellent yields. Structurally divergent aliphatic, aromatic, heterocyclic primary and secondary amines were converted to the corresponding N,N′,N″-trisubstituted guanidines using optimal conditions. The catalyst was easy to handle even under atmospheric conditions and can be easily recovered by centrifugation and reused for five cycles with consistent activity.     

Copper(II) tetrafluoroborate as a novel and highly efficient catalyst for N-tert-butoxycarbonylation of amines under solvent-free conditions at room temperature

Commercially available copper(II) tetrafluoroborate hydrate was found to be a highly efficient catalyst for chemoselective N-tert-butoxycarbonylation of amines with di-tert-butyl dicarbonate under solvent-free conditions and at room temperature. Various aromatic amines were protected as their N-tert-butyl carbamates in high yields and in short times. No competitive side reactions such as isocyanate, urea, and N,N-di-t-Boc formation was observed. Chemoselective N-tert-butoxycarbonylation was achieved with substrates bearing OH and SH groups. Chiral α-amino acid esters afforded the corresponding N-t-Boc derivatives in excellent yields.     

Microwave-assisted synthesis of N-glycolylneuraminic acid derivatives

A rapid, efficient and scalable synthesis of biologically-relevant N-glycolylneuraminic acid derivatives from the natural N-acetyl (Neu5Ac) precursors has been developed. Microwave irradiation provides accelerated de-N-acetylation compared to more traditional methods, with optimised NaOH-promoted de-N-acetylation in only 15 min. The prepared amines were readily re-N-acylated to afford the corresponding N-glycolyl (Neu5Gc) analogues.     

Synthesis of tetrahydrophthalazine and phthalamide (phthalimide) derivatives via palladium-catalysed carbonylation of iodoarenes

1,2,3,4-Tetrahydrophthalazin-1-one and 1,2,3,4-tetrahydrophthalazin-1,4-dione derivatives were synthesised in high (up to 85%) and low yields using 2-iodobenzyl bromide and 1,2-diiodobenzene as bifunctional substrates, respectively. Iodoarenes, carbon monoxide and various hydrazine derivatives as N-nucleophiles were used in a three-component palladium-catalysed cascade hydrazinocarbonylation. A similar palladium-catalysed reaction, the aminocarbonylation of 1,2-diiodobenzene, resulted mainly in the formation of two types of major products depending on the amine N-nucleophiles: the use of primary amines yielded N-substituted phthalimides in double carbonylation, while secondary amines react with one of the iodoarene functionalities affording the corresponding 2-iodobenzamides. Due to double carbon monoxide insertion at one or both iodoarene functionalities, ketocarboxamide-carboxamide or bis-ketocarboxamide derivatives could be isolated by the modification of the reaction conditions. Some mechanistic details of the ring-closure reactions and the conditions leading to side-products are also discussed.     

Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether

Eliglustat (Cerdelga^®, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihydroxylation and diastereoselective amination of chiral para-methoxycinnamyl benzyl ethers using chlorosulfonyl isocyanate as the key steps. Notably, the reaction between syn-1,2-dibenzyl ether 6 and chlorosulfonyl isocyanate in the mixture of toluene and hexane (10:1) afforded syn-1,2-amino alcohol 5 at a 62% yield with a diastereoselectivity > 20:1. This observation can be explained by competition between the S_Ni and the S_N1 mechanisms, leading to the retention of stereochemistry.     

High-yielding synthesis of 1-isoindolinone derivatives via palladium-catalysed cycloaminocarbonylation

1-Isoindolinone derivatives were synthesised in high yields (up to 89%) by using 2-iodobenzyl bromide and 2-iodobenzylamine as bifunctional substrates in palladium-catalysed carbonylation. Depending on the N-nucleophiles, two types of compounds were synthesised with 2-iodobenzyl bromide: the use of primary amines, including amino acid methylesters, resulted in the formation of N-substituted 1-isoindolinones, while secondary amines react both with the benzyl bromide and iodoarene moieties resulting in the corresponding ortho-(N-piperidino/morpholinomethyl)-benzamides. The parent 1-isoindolinone was obtained in a facile, highly chemoselective intramolecular aminocarbonylation of 2-iodobenzylamine. The mechanistic details of the ring-closure reaction and the conditions leading to side-products are discussed as well.     

3,3-Dimethoxypropylsulfonyl Group: A new versatile protecting and activating group for amine synthesis

3,3-Dimethoxypropylsulfonyl (Dimps) chloride was prepared and used as a new versatile sulfonating agent for ammonia, primary and secondary amines to afford corresponding Dimps-amides in excellent yields. The resulting N-nonsubstituted and N-monosubstituted Dimps-amides, activated amines, were alkylated satisfactorily under new Mitsunobu conditions. The Dimps group was removed by treatment in aqueous solution under acidic followed by basic conditions. Furthermore, epilachnene, the defensive droplets from the Mexican bean beetle, Epilachna varivestis, was synthesized utilizing this Dimps methodology in short steps.     

Asymmetric hydrogenation of N-alkyl and N-aryl ketimines using chiral cationic Ru(diamine) complexes as catalysts: the counteranion and solvent effects,and substrate scope

Asymmetric hydrogenation of N-alkyl and N-aryl ketimines catalyzed by chiral cationic η⁶-arene-(N-monosulfonylated diamine) Ru(II) complexes has been investigated. Strong counteranion and solvent effects on the enantioselectivity were observed. The ruthenium catalyst bearing non-coordinating BArF^? anion was found to be particularly effective for the hydrogenation of acyclic and exocyclic N-alkyl ketimines in the presence of (Boc)₂O in dichloromethane or even under solvent-free conditions, providing chiral amines with up to >99% ee and full conversions. Alternatively, the ruthenium catalyst bearing achiral phosphate anion together with corresponding phosphoric acid as the additive was also efficient for the hydrogenation of N-alkyl ketimines in the absence of (Boc)₂O with excellent enantioselectivities and full conversions. For N-aryl ketimines lower enantiomeric excesses were observed by using the ruthenium catalyst bearing BArF^? anion. This catalytic protocol thus provides a facile and practical access to optically active amines and has been successfully employed in the gram-scale synthesis of enantiomerically pure (+)-sertraline.     

N-Benzyloxycarbonylation of amines in the ionic liquid [TPA][l-Pro] as an efficient reaction medium

An efficient method for the N-benzyloxycarbonylation of amines is described. The reaction of amines with Cbz-Cl in the ionic liquid [TPA][l-Pro] afforded the corresponding N-Cbz derivatives in excellent yields. The method is versatile for the preparation of a wide variety of N-Cbz derivatives of aliphatic and aromatic amines.     

Aminolysis of glycal-derived allyl epoxides and activated aziridines. Effects of the absence of coordination processes on the regio- and stereoselectivity

The addition of primary and secondary aliphatic amines to glycal-derived allyl epoxides is completely 1,2-regio- and anti-stereoselective, whereas mixtures of the corresponding anti-1,2- [3-N-(substituted-amino) glycals] and anti-1,4-addition products (N-glycosyl amines) are obtained with N-(mesyl)-aziridines. In this way, structural moieties, otherwise difficult to synthesize, are obtained by means of a very simple protocol. The regio- and stereoselectivity observed with epoxides is the consequence of an isomerization process, whereas the result obtained with aziridines is explained by the absence of an effective substrate-nucleophile (amine) coordination.     

Synthesis of vicinal (alkylamino)alkynylcyclopropanes from geminal alkynyl(chloro)cyclopropanes

New N-Boc-alkyl(2-alkynylcyclopropyl)amines were synthesized from 1-alkynyl-1-chlorocyclopropanes and N-Boc- alkylamines under the action of Bu^tOK in DMSO, the intermediates having been the corresponding conjugated alkynylcyclopropenes. The Boc-derivatives can be converted into free secondary 2-alkynylcyclopropylamines, as well as β-lithiated with subsequent alkylation.     

Base catalyzed cyclization of N-aryl and N-alkyl-O-propargyl carbamates to 4-alkylidene-2-oxazolidinones

The base catalyzed cyclization of N-aryl and N-alkyl-O-propargyl carbamates is studied in detail. The effect of various bases and solvents on the efficacy of this cyclization reaction is analyzed and a new base-solvent system (LiOH in DMF) for effective cyclization of these carbamates is reported. A number of differentially substituted O-propargyl carbamates were cyclized to the corresponding 2-oxazolidinones under these conditions. The reaction conditions reported here are mild and no side reactions were observed in any of the substrates studied. A propargyl carbonate group was unaffected during the course of the cyclization of the O-propargyl carbamate group. The propargyl carbamates were prepared from the corresponding alkyl or aryl amines and the corresponding propargyl chloroformate, resulting in oxazolidinones diversely substituted at the nitrogen atom. N-Aryl-O-propargyl carbamates cyclized readily to the corresponding oxazolidinones with LiOH in DMF, whereas N-alkyl-O-propargyl carbamates reacted slowly under the same conditions. O-Propargyl carbamates substituted at the 1-position tend to cyclize faster whereas those substituted at 3-position cyclize considerably slower than the unsubstituted carbamates.