Benzotriazoles ester synthesis

In the first step amine 11 is coupled with carboxylic acid 15 to form an amide The method employed here for coupling an a-chiral carboxylic acid with an amine was developed in the context of peptide synthesis. Its success is based on DCC-mediated formation (see Chapter 5) of the reactive 1-hydroxy benzotriazole ester 55, which reacts with an amine to give the corresponding amide. In most cases reaction takes place without raccmi/ation, and often in the absence of side reactions that cause other procedures to The alcohol is converted into a silyl ether in the second step. 

T1 resin traceless linker [131-134], synthesis of phenols [135], biaryls, alkyl arenes [136, 137], azides [138], aromatic hydrazines, halides [cf. 128, 129, 139], ester, azo compounds, cinno-lines [140], benzotriazoles [141]... 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

An efficient synthesis of 2Ff-azirines 6 substituted with a phosphate group is described. Its key step is an alkaloid catalyzed Neber reaction of -ketoxime tosylates 5 (equation 3) . Similarly, azirines containing an ester group in position 2 were obtained from tosy-lated oximes . A novel approach to substituted 2Ff-azirines using benzotriazole (Bt) methodology was recently presented. The reaction of benzotriazole oxime tosylates formed from the oxime 7 and TsCl with aqueous KOH yielded 2-(benzotriazol-l-yl)-2H-azirines. 

Oximino cyanoacetate or malonate esters (Me02CC(CN)=N0Ts or (Me02C)2C= NOCOPh) reacted with diazoaUcanes (RCHN2) to give unstable 1,2,3-triazolines . Synthesis of Al-imidoylbenzotriazoles via benzotriazole-mediated Beckmann rearrangement of oximes is also described . ... 

The utility of carbodiimide reagents was too important to consider abandoning them. Instead, it rapidly became obvious that carbodiimide activation could be used to prepare in situ active esters. Numerous nucleophilic additives were discovered and prepared for use in these reactions. The most important of these additives was 1,2,3-benzotriazol-l-ol (HOBt, 1), first reported for use in peptide synthesis by Konig and Geiger in 1970.[2(l As an example of a typical result, 1.2 equivalents of HOBt was added to the DCC coupling of Boc-Leu-Phe-OH to H-Val-OtBu in DMF as a solvent. Less than 1% of the l-d-l epimerized tripeptide was formed. When the reaction was carried out in the absence of HOBt, the amount of l-d-l product formed was 14.3%. Addition of HOBt to DCC reactions converts the intermediate G-acylisourea (2) (and any symmetrical anhydride) into the HOBt active ester 3 (Scheme 8). 

The synthesis of (-t-)-polyoxin J 14 is completed by selective ester hydrolysis with aqueous lithium hydroxide. The resulting carbamoylpolyoxamic acid was then coupled with the protected thymine polyoxin C 8 with the BOP reagent (Castro s reagent)14 (benzotriazol-1 -yloxytris(dimethyl-amino)phosphonium hexafluoro-phosphate) 37 to furnish the peptide derivative in 63 % yield. 

N-Substituted benzotriazole intermediate (77) is an excellant synthon for the synthesis of 2-ethoxy-2-vinylcyclopropanecarboxylate esters (78) [95JOC6], 1-Propargylbenzotriazole was reacted with bromoacetophenone to provide the novel 2-(benzotriazolomethyl)furan (80) in 60% yield [95JOC638]. Annelated N-aminotriazoles, on oxidation, are a good source of cyclic alkynes as illustrated for the reaction of aminotriazolotropone (80) with 4-phenyloxazole to generate the furyl[3,4-cf]tropone (82) from a Diels-Alder intermediate with facile loss of benzonitrile [94TL8421 ]. 

First, the (/f)-2-methylcysteine compound 5 is N- and S-protected and coupled with the threonine methyl ester to the hydroxyamide 57 with benzotriazole-1 -yloxy-tripyrrolidino-phos-phonium hexafluorophosphate (pyBOP) [16]. Burgess reagent [17] turns out to be the best choice for the conversion of 57 into 58. The use of Burgess reagent for the synthesis of oxazo-line was examined extensively by Wipf et al. [ 18]. For other methods of synthesizing oxazoles, which were developed in connection to the synthesis of calyculin A, see [19]. 

In the absence of base, active esters of both N-alkoxycarbonyl amino acids and N -protected peptides undergo anninolysis with preservation of chiral integrity. There is ample evidence to substantiate this statementP d and no evidence to the contrary. But there is a wealth of accumulated evidence that active esters undergo isomerization when left in the presence of tertiary annine.t In this regard, 4-nitrophenyl esters are much more sensitive than trichlorophenyl esters and piperidino esters are exceptions in that they are unaffected by tertiary anoine.W The isomerization recently observed in the TBTU-mediated couplings of Fmoc-Cys(R )-OH in the presence of 1,2,3-benzotriazol-l-ol in continuous flow solid-phase synthesis is a further example of this phenomenon. The result can be attributed to the effect of tertiary amine on the benzotriazolyl ester that is formed by capture of the acyluronium intermediate before it has time to be aminolyzed. 

This reagent, benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (14, PyBOP)P l (Scheme 4), was designed in order to avoid the formation of toxic HMPA during acylation. As with BOP, it is assumed that the first step is the carboxylic acid activation which involves formation of an acyloxyphosphonium salt.P This initial salt is then attacked by the benzotriazolyloxy anion to form the benzotriazolyl active ester which then reacts with the amino component. PyBOP can easily replace the BOP reagent and is especially suitable for solid-phase peptide synthesis. It is soluble in a wide range of solvents such as DMF, di-chloromethane, THF, and NMP. PyBOP is more useful in peptide synthesis on solid support than in solution. The byproduct, tris(pyrrolidino)phosphine oxide is partially water-soluble and is easily removed by washing. PyBOP is used under the same experimental conditions as BOP. Note that PyBOP is a white, crystalline and non-hygroscopic solid. It can be kept as a solid, but solutions of PyBOP cannot be stored for more than 24 hours. 

In 1984, when the 430A was introduced, the only scale was 0.50 mmol which used 2 mmol Boc amino acid cartridges. In 1987, a 7-mL reaction vessel was created for a 0.10 mmol synthesis using Innmol of Boc amino acid. These cycles were called the small-scale rapid cyclesh l since the time was 20 minutes compared to 45 minutes for the standard cycles. Also in 1987, Fmoc cycles using HOBt active esters were released. In 1992, Boc cycles with 2-(l//-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU) activation for the 430A which did not have a neutralization step after the TFA deprotection, was reported.t Neutralization of the TFA-salt of the resin-bound amino... 

A synthesis of alkynes from esters via a one-carbon homologation is by reaction with 1-lithiomethylbenzotriazole, followed by elimination of the derived benzotriazol-1-ylmethyl ketone tosylhydrazones. ... 

Stereoselective olefination of carboxylic eaters or synthesis of allylamines from a-amino acid esters mediated by benzotriazole(Bt) derivatives. 

Functional group exchanges. TiCla serves as a catalyst in the conversion of THP ethers, silyl ethers, and propargyl esters to the corresponding esters and ethers. A direct synthesis of a-(benzotriazol-l-yl)alkyl ethers involves treatment of dialkyl ethers with 1-chlorobenzotriazole andTiCl4. ... 

Peptide synthesis. CoupUng reactions in peptide synthesis using active esters are greatly accelerated in the solution phase or the solid phase by addition of 1 -hydroxy benzotriazole. 

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