Benzotriazoles, acyl, acylating reagent

Acylbenzotriazoles 162 are efficient C-acylation reagents for the regioselective conversion of ketone enolates into P-diketones . Diethyl(l-benzotriazolmethyl)phosphinate (163) was found to be a convenient reagent for the stereoselective preparation of (E)-l-(l-alkenyl)benzotriazoles <00SC1413>. The novel three-carbon synthon 1-(1//-133-... 

Selective trifluoroacetylation of primary amines in the presence of secondary amines can be accomplished by reaction with a stoichiometric amount of ethyl trifluoroacetate (bp 60-62 C) in THF, acetonitrile or dioxane at 0 C. The product is simply isolated by evaporation of the solvent and liberated ethanol. " Perhaps the most common method entails acylation of the amine with trifluoro-acetic anhydride in the presence of a suitable base such as triethylamine or pyridine in dichloromethane [Scheme 8.26]. New reagents for the N-trifluoro-acetylation of amines include -(trifluoroacetyl)succinimide, a solid and storable reagent, /V-(trifluoroacetoxy)succinimide, which must be stored in a frozen benzene matrix, and l-(trifluoroacetyl)-l,2,3-benzotriazole. The latter reagent is a stable, crystalline reagent (mp 89-91 C) prepared in quantitative... 

A further application of the benzotriazole linker is the synthesis of fi-diketones 382. Polymer-supported benzotriazoles 371 were transformed into the corresponding azolides which were cleaved with various ketone hhio eno-lates to build diketones 382 [261]. Other cleavage reactions with nucleophiles should be possible as benzotriazole auxiliaries are often used as advantageous N, C-, S- and 0-acylating reagents [262]. A well-known application is the solid phase synthesis of unsymmetric ureas (R = NR2) with secondary amines as cleaving nucleophiles [258]. 

This reagent combination also converts carboxylic acids to acyl chlorides (see Section 3.4.1). The mechanistic basis for the special effectiveness of benzotriazole has not yet been determined, but it seems likely that nucleophilic catalysis is involved. Sulfinyl ester intermediates may be involved, because Z-2-butene-l,4-diol gives a cyclic sulfite ester with one equivalent of reagent but the dichloride with two equivalents. 

Treated with a base, l-(arylacetyl)benzotriazoles 954 eliminate benzotriazole to form ketenes 955. When no other reagent is added, ketene 955 is acylated by another molecule of 954 to produce ot-ketoketene 956 which upon addition of water and decarboxylation during the work-up is converted to symmetrical dibenzyl ketone 957... 

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. 

Acyl anion equivalents. Benzotriazol-l-ylmethyl methyl sulfide can undergo consecutive C-alkylations. The products are readily hydrolyzed with acidic aqueous methanol to give ketones. A related process involving alkylation and sulfenylation followed by treatment with a Grignard reagent to eliminate benzotriazole completes the synthesis of ketene dithioacetals. ... 

A -Acyl benzotriazoles very effectively acylate pyrrole at C-2 using TiCLt catalysis TlPS-pyrrole is acyl-ated with this reagent at C-3. ... 

Meutermans and Alewood [48] reported the solid-phase synthesis of tetrahydroisoquinolines 13 and dihydroisoquinolines 13a using the Bischler-Napieralski reaction (Fig. 5). The polystyrene resin-bound deprotected L-3,4-dimethoxyphenylalanine was acylated with acetic acid derivatives using N- [(IH-benzotriazol-1 -yl)(dimethylamino)methylene] -iV-methylmethana-minium hexafluorophosphate A-oxide (HBTU) as a coupling reagent. The product obtained was then treated with phosphorus oxychloride under optimized conditions to afford a Bischler-Napieralski cyclization. Hutchins and Chapman [49] reported the synthesis of tetrahydroisoquinolines 13b and 4,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridines 14 via cyclocondensation of the appropriate dipeptidomimetic with various aldehydes (Fig. 6). 

Both thiophene acylation (Scheme 19) and alkylation (see Sect. 2.2.3) [39] were achieved by application of benzotriazole derivatives as active reagents. Thus,... 

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