Selective Analysis of Secondary Amines Using Liquid Chromatography with Electrochemical Detection (LC‐EC)

In a mixture of primary and secondary aliphatic amines, the primary amines were derivatized (masked) with o‐phthalaldehyde (OPA) followed by derivatization of the remaining secondary amines with ferrocenecarboxylic acid chloride (FAC). The “tagged” amines were analyzed by LC‐EC (liquid chromatography with electrochemical detection) using in‐series dual electrode detection. Chemically‐reversible oxidation of the FAC tagged secondary amines and their subsequent complementary oxidation and reduction signals coupled with chemically‐irreversible oxidation of OPA tagged primary amines provided the selectivity for quantitative secondary amine analysis. The procedure was also applied for the selective identification of fragment 4–11 (N‐terminus‐proline) of Substance P in the presence of other Substance P fragments with primary amino acids as their N‐termini.     

Investigation of some biologically relevant redox reactions using electrochemical mass spectrometry interfaced by desorption electrospray ionization

Recently we have shown that, as a versatile ionization technique, desorption electrospray ionization (DESI) can serve as a useful interface to combine electrochemistry (EC) with mass spectrometry (MS). In this study, the EC/DESI-MS method has been further applied to investigate some aqueous phase redox reactions of biological significance, including the reduction of peptide disulfide bonds and nitroaromatics as well as the oxidation of phenothiazines. It was found that knotted/enclosed disulfide bonds in the peptides apamin and endothelin could be electrochemically cleaved. Subsequent tandem MS analysis of the resulting reduced peptide ions using collision-induced dissociation (CID) and electron-capture dissociation (ECD) gave rise to extensive fragment ions, providing a fast protocol for sequencing peptides with complicated disulfide bond linkages. Flunitrazepam and clonazepam, a class of nitroaromatic drugs, are known to undergo reduction into amines which was proposed to involve nitroso and N-hydroxyl intermediates. Now in this study, these corresponding intermediate ions were successfully intercepted and their structures were confirmed by CID. This provides mass spectrometric evidence for the mechanism of the nitro to amine conversion process during nitroreduction, an important redox reaction involved in carcinogenesis. In addition, the well-known oxidation reaction of chlorpromazine was also examined. The putative transient one-electron transfer product, the chlorpromazine radical cation (m/z 318), was captured by MS, for the first time, and its structure was also verified by CID. In addition to these observations, some features of the DESI-interfaced electrochemical mass spectrometry were discussed, such as simple instrumentation and the lack of background signal. These results further demonstrate the feasibility of EC/DESI-MS for the study of the biology-relevant redox chemistry and would find applications in proteomics and drug development research.     

3 d Transition Metal‐Catalyzed Hydrogenation of Nitriles and Alkynes

Selective hydrogenation of nitriles and alkynes is crucial considering the vast applications of reduced products in industries and in the synthesis of bioactive compounds. Particularly, the late 3d transition metal catalysts (manganese, iron, cobalt, nickel and copper) have shown promising activity for the hydrogenation of nitriles to primary amines, secondary amines and imines. Similarly, semihydrogenation of alkynes to E‐ and Z‐alkenes by 3d metals is adequately successful both via the transfer hydrogenation and by using molecular hydrogen. The emergence of 3d transition metals in the selective synthesis of industrially relevant amines, imines and alkenes makes this protocol more attractive. Herein, we provide a concise overview on the late 3d transition metal‐catalyzed hydrogenation of nitriles to amines and imines as well as semihydrogenation of alkynes to alkenes.     

Analytical Aspects of Reactions of Primary Aromatic Amines with <Emphasis Type="Italic">p</Emphasis>-Dimethylaminocinnamic Aldehyde in the Presence of Surfactant Ions and Micelles

The effect of surfactants on reactions of primary aromatic amines with p-dimethylaminocinnamic aldehyde is studied. It is shown that the performance characteristics of the photometric determination of primary aromatic amines with p-dimethylaminocinnamic aldehyde can be substantially improved by using anionic surfactant micelles. On the basis of the observations, it is shown that anionic surfactants play a multiple role in the systems in study. Namely, surfactant anions select photometrically significant protonated quinoid forms of the condensation products of primary aromatic amines with p-dimethylaminocinnamic aldehyde (at a premicellar concentration) to form poorly soluble ion pairs. Next, anionic surfactant micelles dissolve them to form-intensely colored solutions that possess aggregative stability. Additionally, anionic surfactants increase the condensation rate. Procedures are developed for photometric and test determinations of aniline and its toxic and medicinal derivatives in the environmental samples, pharmaceutical formulations, and biological fluids. The procedures exhibit low detection limits; they are simple and precise.__________Translated from Zhurnal Analiticheskoi Khimii, Vol. 60, No. 5, 2005, pp. 471–478.Original Russian Text Copyright © 2005 by Doronin, Chernova, Gusakova.     

Synthesis of Highly Enantioenriched Sulfonimidoyl Fluorides and Sulfonimidamides by Stereospecific Sulfur–Fluorine Exchange (SuFEx) Reaction

Sulfonimidamides present exciting opportunities as chiral isosteres of sulfonamides, with potential for additional directional interactions. Here, we present the first modular enantioselective synthesis of sulfonimidamides, including the first stereoselective synthesis of enantioenriched sulfonimidoyl fluorides, and studies on their reactivity. A new route to sulfonimidoyl fluorides is presented from solid bench-stable, N-Boc-sulfinamide (Boc=tert-butyloxycarbonyl) salt building blocks. Enantioenriched arylsulfonimidoyl fluorides are shown to be readily racemised by fluoride ions. Conditions are developed, which trap fluoride and enable the stereospecific reaction of sulfonimidoyl fluorides with primary and secondary amines (100 % es, es=enantiospecificity) generating sulfonimidamides with up to 99 % ee. Aryl and alkyl sulfonimidoyl fluoride reagents are suitable for mild late stage functionalisation reactions, exemplified by coupling with a selection of complex amines in marketed drugs.     

A Hydrazone‐Based exo‐Directing‐Group Strategy for β C−H Oxidation of Aliphatic Amines

Described is a new hydrazone‐based exo‐directing group (DG) strategy developed for the functionalization of unactivated primary β C?H bonds of aliphatic amines. Conveniently synthesized from protected primary amines, the hydrazone DGs are shown to site‐selectively promote the β‐acetoxylation and tosyloxylation via five‐membered exo‐palladacycles. Amines with a wide scope of skeletons and functional groups are tolerated. Moreover, the hydrazone DG can be readily removed, and a one‐pot C?H acetoxylation/DG removal protocol was also discovered.     

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).     

Catalytic Promiscuity of Transaminases: Preparation of Enantioenriched β‐Fluoroamines by Formal Tandem Hydrodefluorination/Deamination

Transaminases are valuable enzymes for industrial biocatalysis and enable the preparation of optically pure amines. For these transformations they require either an amine donor (amination of ketones) or an amine acceptor (deamination of racemic amines). Herein transaminases are shown to react with aromatic β‐fluoroamines, thus leading to simultaneous enantioselective dehalogenation and deamination to form the corresponding acetophenone derivatives in the absence of an amine acceptor. A series of racemic β‐fluoroamines was resolved in a kinetic resolution by tandem hydrodefluorination/deamination, thus giving the corresponding amines with up to greater than 99 % ee. This protocol is the first example of exploiting the catalytic promiscuity of transaminases as a tool for novel transformations.     

Synthesis and spectral studies of macrocyclic Cu(II) complexes by reaction of various diamines,copper(II) perchlorate and 1,4-bis(2-carboxyaldehyde phenoxy)butane

Six macrocyclic complexes, were synthesized by reaction of 1,4-bis(2-carboxyaldehyde phenoxy)butane and various amines and their copper(II) perchlorate complexes were synthesized by template effect reaction of 1,4-bis(2-carboxyaldehyde phenoxy)butane, Cu(ClO₄)₂?·?6H₂O and amines. The metal-to-ligand ratios were found to be 1?:?1. Cu(II) metal complexes are 1?:?2 electrolytes as shown by their molar conductivities (Λ_M) in DMF (dimethyl formamide) at 10^?3?M. The Cu(II) complexes are proposed to be square planar based on elemental analysis, FT–IR, UV–Vis, magnetic susceptibility measurements, molar conductivity measurements, and mass spectra.     

Cyclic hydroxamic acids derived from quinazoliue

The action of various acylating agents on 2-aminobenzohydroxamic acid afforded 3-hydroxy-4(3H)quinazolinones (hydroxamic acids) as well as several ethers and esters from them were prepared and their spectroscopic properties analyzed. Secondary amines, as well as one equivalent of alkali, on 2-halomethyl-3-hydroxy-4(3H)quinazolinone lead to the formation of a dimer(XI). In this respect the behaviour of secondary amines is different from that of primary amines. Some new 3-hydroxy-2-4(1H,3H)-quinazolidinediones are described.     

Synthesis and Use of 2H‐Azirin‐3‐amines as Dipeptide Synthons

The synthesis of the new 2H‐azirin‐3‐amines (‘3‐amino‐2H‐azirines') 11, 20, 28 , and 33 as dipeptide synthons is described. The reactions of the starting amides with Lawesson reagent gave the corresponding thioamides, and consecutive treatment with COCl₂, 1,4‐diazabicyclo[2.2.2]octane (DABCO), and NaN₃ led to the desired products. It is shown that these 2H‐azirin‐3‐amines can conveniently be used as building blocks of the dipeptides Aib‐(Me)Axx (Axx=alanine, valine), Aib‐Homoproline, and Iva‐Pro in the synthesis of several model peptides. However, some limitations apply for the synthesis of such 2H‐azirin‐3‐amines. The starting material for the azirine synthesis, the corresponding thioamides, cannot generally be synthesized, and the 2H‐azirin‐3‐amines could not be obtained in all cases from the thioamides prepared.     

Thiocarbamoylation of amine-containing compounds

Thiocarbamoylation of aliphatic amines with tetramethylthiuram disulfide (TMTD) was studied. The reactions were established to proceed according to a two-stage mechanism. In the first stage,S-(thiocarbamoyl)thiohydroxylamines and dimethyl dithiocarbamates are formed. The latter exist in equilibrium with dimethyldithiocarbamic acid, which can undergo decomposition to give dimethylamine and carbon disulfide. In the second stage, several competitive transformations of these intermediates into the final products occur,viz., (1) the reactions of CS₂ with primary amines on heating (70–110 °C) yield mixed and symmetrical thioureas and the reactions of CS₂ with secondary amines give symmetrical dithiocarbamates, and (2) insertion of CS₂ intoS-(thiocarbamoyl)thiohydroxylamines affords thiuram disulfides. Thiuram disulfides formed from primary amines decompose to give isothiocyanates, which are converted into thioureas by condensation with amines, whereas thiuram disulfides which are obtained in the reactions with secondary amines and which cannot form thioureas react with amines analogously to TMTD. For Part 4, see Ref. 1. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 334–342, February, 2000.     

HPLC post column derivatization of aromatic amines usingN-methyl-9-chloroacridinium triflate

An HPLC post column chemical derivatization procedure based on the interaction between an acridinium triflate and amines to form highly colored derivatives on-line is described for the determination of aromatic amines. Benzocaine and butesin, local anesthetic agents that contain the aromatic amine group, were used as model compounds. Reversed-phase HPLC conditions were developed for both the separation of analytes and the reaction between analytes and the acridinium triflate in the system. Three-dimensional knitted teflon shape coils and the internal diameter and length of the coils were important parameters in reducing band broadening and background noise.N-Methyl-9-chloroacridinium triflate was shown to be applicable to the determination of primary aromatic amines, selected secondary aromatic amines, hydrazides, and hydrazines. Application of the on-line chemical derivatization procedure to the analysis of pharmaceutical dosage forms containing procainamide (primary aromatic amine), isoniazid (hydrazide), and hydralazine (hydrazine) is also described.     

Tailoring D‐Amino Acid Oxidase from the Pig Kidney to R‐Stereoselective Amine Oxidase and its Use in the Deracemization of α‐Methylbenzylamine

The deracemization of racemic amines to yield enantioenriched amines using S‐stereoselective amine oxidases (AOx) has recently been attracting attention. However, R‐stereoselective AOx that are suitable for deracemization have not yet been identified. An R‐stereoselective AOx was now evolved from porcine kidney D ‐amino acid oxidase (pkDAO) and subsequently use for the deracemization of racemic amines. The engineered pkDAO, which was obtained by directed evolution, displayed a markedly changed substrate specificity towards R amines. The mutant enzyme exhibited a high preference towards the substrate α‐methylbenzylamine and was used to synthesize the S amine through deracemization. The findings of this study indicate that further investigations on the structure–activity relationship of AOx are warranted and also provide a new method for biotransformations in organic synthesis.     

Synthesis and properties of derivatives ofsym-triazine. 16. Synthesis of amine and diamine derivatives ofsym-triazine containing sterically hindered phenol groups from 6-alkyl(aryl)thio-2,4-bis(trichloromethyl)-sym-triazine

The reaction of 6-alkyl(aryl)thio-2,4-bis(trichloromethyl)-sym-triazines with ammonia and primary and secondary amines is studies. It is shown that, depending on the reaction conditions, the replacement of either one or both of the trichloromethyl groups takes place. 6-alkyl(aryl)thio-2,4-diamono-sym-triazines containing sterically hindered phenol groups are synthesized.I. M. Gubkin State Petroleum and Gas Academy, Moscow, 117917. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 224–231., Ferbruary, 1995. Original article submitted December 21, 1994.     

Interactions between Amines and Phospholipids: A Chromatographic Study on Immobilized Artificial Membrane (IAM) Stationary Phases at Various pH Values

The chromatographic capacity factors (log k′) for 23 amines were measured by High Performance Liquid Chromatography (HPLC) on a stationary phase composed of phospholipids, the so‐called `Immobilized Artificial Membrane' (IAM). The chromatographic behaviour of the compounds, which consist of primary, secondary, and tertiary amines, and compounds with endocyclic amino functions, was studied with eluents at various pH values (7.0, 5.5, and 3.0). The results were compared both to the octanol/buffer partition values of neutral forms (log P) and to those of mixtures of neutral and ionised forms, existing at the three pH values above mentioned (log D^7.0, log D^5.5, and log D^3.0). At pH 7.0, the log k′ of all secondary and tertiary amines overlapped with those previously observed for neutral isolipophilic compounds. This behaviour was also observed for primary amines, but only for compounds fully ionised at this pH. In contrast, the partially ionised primary amines at pH 7.0 and the compounds with an endocyclic amino function both showed stronger interactions with phospholipids than expected on the basis of log P. The changes in retention observed with eluents at pH 5.5 indicated that retention varies with the ionisation degree of the analytes. At pH 3.0, the interaction between phospholipids and the ionised forms of the amines considered was impaired probably by a change in the charges on the IAM surface. The present study indicates that phospholipids are a partitioning phase that better accommodates the neutral forms of primary amines than does octanol. Moreover, the phospholipid phase is much less sensitive to the ionisation of analytes than octanol, but only at pH 7.0 and 5.5; indeed, the ionised forms of all the amines considered are retained to the same extent as expected for hypothetical neutral isolipophilic compounds. We can thus conclude that, for amines, the partition scale in phospholipids is distinct from the one in octanol.     

Chloroaromatic ether amines

A new and useful class of aromatic amines, based on multichlorinated benzenes and polyphenyls, has been developed. The amines are prepared by reacting the alkali metal salt of p-aminophenol with the chloroaromatics under nucleophilic substitution reaction conditions. Oligomeric amines can be obtained by condensing, e.g., the dialkali salt of bisphenol A and the alkali metal salt of p-aminophenol with the chloroaromatics. The products are mixtures of mono-, di-, and triamines, as a result of the complex functionalities of the chloroaromatics employed. Unique features of the amines include: (1) flame-retarding characteristics; (2) markedly reduced amine reactivity (compared with aniline); (3) thermal stability; (4) good solubility in the usual organic solvents.     

Amine-induced rearrangements of 2-bromo-1-(1H-indol-3-yl)-2-methyl-1-propanones: A new route to α-substituted indole-3-acetamides, β-substituted tryptamines, α-substituted indole-3-acetic acids and indole β-aminoketones

The reaction of 2-bromo-1-(1H-indol-3-yl)-2-methyl-1-propanone ( 1 ) and 2-bromo-1-(1-methyl-1H-indol-3-yl)-2-methyl-1-propanone ( 2 ) with primary amines proceeds in good yields to produce rearranged amides by a proposed pseudo-Favorskii mechanism. These amides in turn can either be reduced to produce β-substituted tryptamines or hydrolyzed to produce substituted indole-3-acetic acids. When the reaction is carried out using bulky primary or secondary amines, β-aminoketones are produced by elimination of hydrogen bromide followed by Michael addition. When hindered secondary amines or tertiary amines are used, elimination to the α,β-unsaturated ketones occurs.     

Steam chromatography of aliphatic and aromatic amines on packed columns with aqueous potassium hydroxide as the stationary liquid phase

Aqueous alkali was proposed as the stationary liquid phase (SLP) for separation of amines by steam chromatography. Characteristic features of retention of amines of various structures were studied. The retention of primary and secondary amines on aqueous potassium hydroxide as the SLP differs fundamentally from that observed with common organic SLP. Primary amines are eluted in the following order,n-pentylamine <n-butyl-amine <n-propylamine <n-hexylamine <n-octylamine for secondary amines, the following sequence was established; diethylamine < dibutylamine < dimethylamine. Higher-boiling tertiary amines containing ethyl andn-butyl radicals are eluted ahead of diamines containing the same radicals. Translated fromIzvestiya Akademii Nau. Seriya Khimicheskaya, No. 8 pp. 1507–1509, August, 1999.