Reactions with N-(1-benzotriazolylcarbonyl)-amino acids. IV. The use of N-(1-benzotriazolylcarbonyl)-amino acid derivates in peptide synthesis

The use of the 1-benzotriazolylearbonyl-(Bte)-group as an N-protecting and N-activating group in the synthesis of peptides was investigated. Removal of the Btc group from N-Btc-amino acids, their esters and amides under acidic conditions is possible, but has no advantages over removal of benzyloxyearbonyl-(Z)-group. N-Btc-amino acid esters react with Z-amino acids or Z-dipeptides yielding Z-dipeptide and Z-tripeptide esters, respcetively. This process is aceompanied with separation of benzotriazole and C02. Advantages and disadvantages of this method of peptide bond formation are discussed

Reactions with 1-Benzotriazolecarboxylic Acid Chloride. VIII. Synthesis of N-Hydroxyisocyanate Derivatives

1,3,5-Trihydroxy-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (5), the trimer of hypothetical acid HO-N=C=O, was synthesized by hydrogenolysis of 1,3,5-tribenzyloxy-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (4). Similarly, the 1-(N-hiydroxycarbamoyl)benzotriazole (6), as »solid HONCO donor«, was prepared by hydrogenolysis of its benzyl derivatives 2. Compound 4 was obtained by trimerization of intermediary N-benzyloxyisocyanate (3), which liberates in the thermal dis-sociation of 1-(N-benzyloxycarbamoyl)benzotriazole (2). In the reaction with 2-phenylethylamine, compound 6 gave N-hydroxy-N\u27-(2-phenylethyl)urea (7)

Reaktionen mit N-(1- Benzotriazolylcarbonyl)-aminosauren.III Synthese von Aminosaure-estern

N-(l-Benzotriazolylcarbonyl)-aminosauren· (Ia-f) reagieren mit Alkoholen unter Abspaltung von Benzotriazol und Kohlendioxid zu den entsprechenden Aminosaure-Estern. (Ila-i). Die Reaktion verlauft bei Raumtemperatur und wird durch Zugabe von Triethylamin beschleunigt

IR Spectroscopy Study of the Amidation Reaction of N-(1-Azolecarbonyl)amino Acids on L-Phenylalanine Derivative Models

Behaviour of N-(1-azolecarbonyl)-L-phenylalanine (Azc-Phe-OH, 1a-d) and L-phenylalanine N-carboxy anhydride (L-Phe-NCA, 6) in the presence of triethylamine (TEA) or cyclohexylamine was followed by IR spectroscopy. IR spectra were recorded in acetonitrile solutions. Attention was focused on characteristic absorptions of CO2 (2340 cm–1) and Azc, COOH or the anhydride group (1850-1600 cm–1). The obtained results corroborate N-carboxy anhydride as an intermediate in amidation reactions of Azc-amino acids

Reaktionen mit N-(1-Benzotriazolylcarbonyl)-aminosaeuren. I. Synthese von Hydantoinen und Hydantoinsaeure-amiden

Die N-(1-Benzotriazolylcarbonyl)-aminosiiuren (I) werden mit Thionylchlorid in die mit der BTCO-gruppe geschutzten Aminosiiure- chloride (II) uberftihrt. Die konnen dann mit verschiedenen Aminen, indirekt uber isolierbare N-(1-Benzotriazolylcarbonyl)- aminosiiureamiden (III), oder direkt in die entsprechend substituierten Hydantoinsiiure-amide (IV) umgesetzt werden. Die Verbindungen III unterliegen bei der Einwirkung von Alkalien einer Cyclisierungs-Eliminierungs-Reaktion und liefern die 3,5-substituierte Hydantoine (V)

Chemistry of 1,3-Dioxepins. XIII. (E)/(Z) Configurational Assignment of 4,7-Dihydro-4-hydroxyimino-6-nitro-1,3-dioxepins

The configuration of oximes 1a and 1b was investigated by chemical and spectroscopic methods. Under the Beckmann rearrangement conditions, using sulfonyl chlorides as reagents, the sulfonic esters 2a-c were obtained. Under more drastic conditions, using PCl5 or P2O5, the only isolated product was 4-nitro-5H-furan-2-on (3). It was also formed as the sole product by hydrolysis of oximes 1a-b, as well as sulfonic ester 2a. The structure of all compounds was determined by one- and twodimensional homo- and hetero-nuclear 1H and 13C NMR correlated spectra: COSY, NOESY, HETCOR and HMBC. Gradient selected differential NOE measurements confirmed that, in dimethylsulfoxide solution, oximes 1a and 1b exist in E-configuration, irrespective of the route of their formation

Chemistry of 1,3-Dioxepins. XII.\u27 4,7-Dihydro-5-nitro-1,3-dioxepins in the Diels-Alder Reaction with 4-Methyloxazole

4,7-Dihydro-5-nitro-l,3-dioxepins 4\u27 prepared by dehydrohalogenation of vic-chloronitro-dioxepanes 2 and/or dehydrohalogenationdemercuration of vic-chloromercurynitro-dioxepanes 3 represent reactive dienophiles in the Diels-Alder cycloaddition with 4-methyloxazole (5), giving pyridoxine (8) intermediates 1,5-dihydro-9-hydroxy- 8-methyl-3H-[1,3]dioxepino[5,6-c]pyridines 6 in poor yields. The side products of this reaction were 4,7-dihydro-4-hydroxyimino- 6-nitro-l,3-dioxepins 7, the structure of which was confirmed by parallel synthesis, i.e. by nitrosation of 4 with ethyl nitrite. The order of reactivity in the series of 5-substituted-4, 7-dihydro- 1,3-dioxepins, calculated by AMI semiempirical method, is predicted to be 5-nitro- > 5-unsubstituted- > 5-cyano- > 5-chloro-4,7-dihydro- 1,3-dioxepin, and it is in agreement with experimental data

Benzotriazole as a Synthetic Auxiliary

Benzotriazole is a very useful synthetic auxiliary with versatile applications in organic chemis¬try. We have used benzotriazole in the synthesis of various heterocyclic compounds (benzoxazine, quinazoline, triazinetrione, hydantoin, oxadiazine and diazepane derivatives), amino acid derivatives, car¬bamates, ureas, semicarbazides, carbazides, sulfonylureas, sulfonylcarbazides, hydantoic acids, non-steroidal antiinflammatory drug (NSAID) and primaquine derivatives, polymer-drug and thiomer-drug conjugates. The results have been published in more than 30 papers and here we give an overview of all syntheses. (doi: 10.5562/cca2124

Synthesis and Reactions of Some Azolecarboxylic Acid Derivatives

Reaction of several azoles with phosgene or triphosgene was studied. Besides benzotriazole (previously described reaction), only indazole, 5-nitroindazole and 5-methylbenzotriazole gave the corresponding 1-azolecarbonyl chlorides 1a-d. Azoles of weak acidity (imidazole, 1,2,3-triazole, 1,2,4-triazole, benzimidazole) could not give stable acyl chlorides, while strong acidic azoles like tetrazole and 4,5,6,7-tetrachlorobenzotriazole did not react at all. Chlorides 1b-d readily reacted with alcohols, amines, amino acids and their esters like the previously described 1-benzotriazolecarboxylic acid chloride (1a), giving 1-azolecarboxylic acid esters (2) or amides (3), N-(1-azolecarbonyl)amino acids (4, 5), their esters (8, 9) or amides (10, 11). However, a significant difference was observed in the reactivity of azole derivatives 2-11 with amines, alcohols and N-protected amino acids or in their stability in acidic and basic aqueous media. Benzotriazole and methylbenzotriazole derivatives were more reactive than indazole or nitroindazole derivatives. The higher reactivity was in correlation with the shift of the IR carbonyl absorption band to higher wave numbers