Benzotriazoles precursors

Hie reactions of 4-chloropyridines and quinolines 17 with benzotriazoles 18 in a modified Graebe-Ullman synthesis give excellent yields of Y arbolines and their benzo-fused derivatives 20. Excellent yields for preparation of the penultimate benzotriazole precursors 19 are reported as well. In the optimized one-pot conditions, the combined neat substrates are heated with microwave irradiation (MW) for short (7-10 min) durations. The crude 19 is treated with H4P2O7 and irradiated futher (4-6 min). The resultant y-carbolines 20 were methylated to form the quaternary salts. These were tested and found to lack DNA intercalation properties <96JOC5587>. 

FIGURE 2.17 Peptide-bond formation from benzotriazol-l-yl-oxy-m s(dimethy-lamino)phosphonium hexafluorophosphate-mediated reactions of Af-alkoxycarbonylamino acids.48 The peptide can originate by aminolysis of either of two precursors the acyloxyphos-phonium cation and the benzotriazolyl ester. 

FIGURE 2.20 Intermediates and their fate in benzotriazol-l-yl-oxyphosphonium salt-mediated reactions. Indirect evidence (Figure 2.21) is not compatible with the tenet that the precursor of the peptide is the benzotriazolyl ester (path C). The evidence indicates that the peptide originates from the acyloxyphosphonium cation (path B). Conversion of this intermediate into the oxazolone (path E) can account for the epimerization that occurs during segment couphngs. 

Benzotriazoles, for example, are accessible from o-aminoaryl-substituted triazenes after a two-step reaction sequence a nucleophilic displacement followed by cleavage/heterocyclization.35 The nucleophilic halide displacement of activated haloarenes is an indispensable tool for the synthesis of highly substituted arenes. Fluoronitroarenes in particular have served as excellent precursors in this transformation. Thus, it was appealing to combine this SNAr reaction with the flexibility of diazonium chemistry. In this case, an immobilized fluoronitrophenyl triazene would be the equivalent of the Sanger reagent. 

Phenyl[2-(trimethylsilyl)phenyl]iodonium triflate (226) has emerged as a superior benzyne precursor i.e., admixture of 226 with tetra-n-butylammonium fluoride (TBAF) enables the generation of benzyne in dichloromethane at room temperature (95JCS(CC)983). When organo azides or -nitrones are available in the reaction medium, high yields of the benzotriazoles 227 or benzisoxazolines 228 are obtained (Scheme 62) (98HC205). 

Benzotriazole-mediated reactions feature in synthetic routes to the isoindolo- and pyrrolo-fused benzothiazole derivatives 272 (e.g. R1 = CH3, R2 = R3 = H) and 273 (e.g. R1 = R3 = H, R2 = Cl) in good overall yields the common precursors were the thioamines 271... 

A-[(A, A -Dialkylamino)alkenyl]benzotriazoles have been shown to be useful precursors to oc-amino radicals, which can subsequently undergo both 5-exo- and 6-exo ring closure on to a,p-unsaturated esters or nitriles.85 For example, exposure of benzotriazole 79 to Sml2 afforded cis-cyclopentane 80 in 70% yield (Scheme 5.52). The mechanism of the cyclisation is believed to involve dissociation of the benzotriazole, thereby generating an iminium cation, which undergoes rapid reduction to the a-amino radical in the presence of Sml2 (Scheme 5.52).85... 

Similarly, aldehyde o-aminophenylhydrazones, available by reduction of the nitro precursors, are converted in the absence of oxygen into 2-substituted benzimidazoles. The reaction is acid catalysed and, although complicated experimentally, gives good yields (67 87%), providing a useful alternative when the 2 substituent may be sensitive. When oxygen is not excluded, benzotriazines form instead 102J. In addition, only fair yields of 1-aminobenzimidazoles are obtained by acid-catalyscd cyclization of N-(o-nitroanilino)-substituted aliphatic amines. Benzotriazoles and benzotriazole... 

An interesting reaction is the N-amination by the reagent of benzotriazole (1) to give 1-aminobenzotriazole (2)," a compound of particular interest as a benzyne precursor (.tee Lead tetraacetate, miscellaneous oxidations). 

Treatment of the solid-supported amino acetals (529) with catalytic PTSA, followed by addition of IH-benzotriazole, resulted in the 2-benzotriazole-substituted piperidines (530) as stable N-acyliminium ion precursors, according to Katritzky [392]. A number of different carbon nucleophiles were then added to the N-acyliminium ions, generated under acid catalysis by either boron trifluoride etherate or camphorsulfonic acid (Scheme 107). 

The benzotriazolyl anion is an excellent leaving group therefore, benzotriazole derivatives have been used extensively as precursors of synthetic components. Furthermore, these reagents are readily obtained from equimolar benzotriazole, an aldehyde, and a secondary amine. A review of synthetic uses of benzotriazole derivatives appeared in 1991. 

Other cation precursors can be used in these reactions. Locher and Peerzada used a benzotriazole unit in a synthesis of tetrahydroisoquinolines. In this reaction, 188 was converted to 189 in 87% yield under very mild conditions. 

A synthesis of 2,3-diarylpyrroles was based on the use of a difunctional phosphine imine which is capable of both Wittig and aza-Wittig condensation. <94J0C4551> The reagent is prepared from benzotriazole, formaldehyde, sodium azide and triphenylphosphine which gives the precursor 13. Reaction with methylidene-triphenylphosphorane and butyllithium generated 14 which reacted with benzil derivatives to give the pyrroles. 

SPPS is often used for the preparation of linear precursors required for NCL. Barany and Tulla-Puche reported NCL on resin to avoid tedious purification steps, usually necessary after each step. The linear precursor was prepared using l-hydroxy-7-aza-benzotriazole (HOAt) or 1-hydroxybenzotriazole (HOBt) and N,... 

Malonic acid serves as a ketene precursor in solid phase N-acetylation of peptides catalyzed by diisopropylethylamine by reaction with the catalyst HBTU (O-benzotriazole-iV, N, N, JV -tetramethyluronium hexafluoro-phosphate) in dg-DMF forming a malonate/tetramethylurea complex that gives ketene and tetramethylurea, as shown by anisidine acetylation (Scheme 4.7). Computational methods favored the pathway shown for ketene generation. This method was used in the acetylation of a variety of resin bound peptides. 

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