Benzotriazoles method development

The present chapter is heavily biased toward benzotriazole as a consequence of numerous synthetic methods developed with the help of this molecule. It has been impossible to cover the field in a comprehensive manner in the pages available. We refer readers to the following reviews that have appeared during the last ten years ... 

This reaction was initially studied by von Baeyer in 1872. It is an acid-catalyzed condensation of aromatic compounds with formaldehyde or formaldehyde derivatives. In normal conditions, the reactive benzene derivatives such as phenols and arylamines are applied to condense with formaldehyde however, a small number of less-reactive aromatics have also been used in this reaction, including benzene, toluene, benzyl chloride,biphenyl, iodobenzene, naphthalene, and mesitylene. Although no yields were given in the early studies, it is reasonable to obtain 70-80% yield for this type of reaction. Many other reactions have been developed to synthesize diarylmethanes, including Katritzky s benzotriazole method, Kochi s dealkylative coupling," Fukuzaw s 1,3-propandiol method, and the reduction method. In general, the condensation occurs at the /tflra-position of substituted aromatics. 

The last two decades have witnessed rapid development of organic synthetic methods based on benzotriazole derivatives. Thus, introduction of benzotriazole moiety to organic molecules provides several practical advantages. Among other benefits, a benzotriazolyl substituent activates the reaction center, stabilizes intermediates, increases regio- and stereoselectivity, and simplifies separation and purification of the products. After the desired molecular assembly is constructed, the bond with benzotriazole is cleaved off to provide the final product. A vast variety of... 

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. 

Katritzky and coworkers have developed two new methods of pyrrole synthesis involving condensation of C3-C4-C5 synthons with Schiff bases to obtain 1,2-diaryl pyrroles. The synthon 2a is obtained by condensation of acrolein, morpholine and benzotriazole, followed by a base-catalyzed elimination. Lithiation gives an anion which adds to the imine. Cyclization occurs on acid treatment. <95TL343> An alternative synthon is obtained by lithiation of 2b. <95S1315>... 

Method 1. The classic developing agent for creating cold tones on bromide papers is amidol. However, PQ developers using organic antifoggant, such as benzotriazole, will also increase the amount of cold image tone in a print (Formulas Paper Developers, Blue-Black Developer). In either case the results are usually very subtle. 

Aryl azides (such as 13) can be easily prepared from their corresponding amines (12) in one or two steps. Three examples are given in Scheme 2a. The most common method is the diazotization of the amine with sodium nitrite under acidic conditions (giving diazonium species 14), followed by addition of sodium azide in an aqueous medium (route i in Scheme 2a) [44], In 2003, the synthetic method was improved by application of triflyl azide (TfN3), which allowed a one-step conversion and gave improved yields (route ii in Scheme 2a) [45]. Recently, the development of sulfonyl azides 15 (with R = imidazole [46] or R = benzotriazole [47]) was reported these proved to be more stable reagents and allowed a conversion under mild conditions (route iii in Scheme 2a). 

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]. 

The phosphonium method was originally developed from derivatives of tris-dimethylaminophosphonium salts for the activation of carboxylic acids [10-13]. The first developed phosphonium salt-type reagents were //-oxo-bis-[tris(dimethyl-amino)phosphonium]-bis-tetrafiuoroborate (Bates Reagent) and benzotriazol-l-yl-N-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP). Although... 

The fluorescence emitted by optical brighteners under ultraviolet light on a thin-layer plate has been utilized as a means of estimating these compounds (method 19). To estimate Tinuvin 326 7(6-butoxy-5-methyl-benzotriazol-2-yl) 3-phenyl-coumarin) in polymer granules, the sample is extracted from the polymer with chloroform. The extract is applied to two Kieselgel G plates and chromatograms are developed with benzene-chloroform (2 3) and benzene, respectively the spots being detected by their fluorescence in ultraviolet radiation. 

A-Alkylation. The title compound is readily converted to N -alkylbenzotriazoles using substitution reactions from the corresponding alkyl halides. ATAlkylbenzotriazoles are usually prepared as a mixture with their A2-substituted isomers by reaction of benzotriazole with alkylation reagents or halogen derivatives in the presence of a base, and are then separated by various purification methods. Recent developments have focused on regioselec-tive methods to afford the AH-substituted benzotriazole in ratios of more than 15 1 over the fV2-isomer. The reaction proceeds in... 

The thermal decomposition of acyl azides into isocyanate intermediates is known as Curtius rearrangement reaction (Scheme 5.2) [27, 28]. Conventionally used general methods to synthesize aroyl azides are limited to diazotization of hydrazides and reactions of NaNs with acid chlorides, mixed anhydrides, and Al-acyl benzotriazoles [35-38]. However, these procedures involve highly reactive chemicals which put significant limitations on functionalities of the substrate. The development of methodologically new, highly functional-group tolerant, catalytic routes to aroyl azides is particularly desirable. 

Another potential problem with DCC is that at the completion of the reaction some DCU remains in solution with the product, necessitating additional purification. Water-soluble carbodiimide derivatives such as l-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide Metho-p-toluenesulffonate and l-Ethyl-3-(3 -dimethylaminopropyl)carbodiimide Hydrochloride (EDCI) obviate this problem, as they are removed by a simple extraction. Many newer coupling agents have been developed for peptide synthesis and other acylation reactions. These include Benzotriazol-l-yloxytris(dimethylamino)phosphonium Hexafluorophosphate (BOP)," 0-Benzotriazol-l-yl-N,N,N, N -tetramethyluronium Hexafluorophosphate (HBTU)," Bis(2-oxo-3-oxazolidinyl)phosphinic Chloride (BOP-Cl), and (1 //-1,2,3-benzotriazol-1 -yloxy)tris(pyrTolidino)phosphonium hexafluorophosphate (PyBOP). In addition to linear and polymeric amides, lactams of various ring sizes have been synthesized using these methods (eq 1)."... 

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