2- pyridine-1 -hydroxybenzotriazole

HOAt, 7-aza-l-hydroxybenzotriazole HATU (CAS Registry No. 148893-10-1), A-[(dimethylamino) (3//-1,2,3-triazolo(4,5- )pyridin-3-yloxy)methylene]-A-methyl-methanaminium hexafluorophosphate, previously known as G-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate. [Note Assignment of structure to HATU as a guanidinium species rather than as a uronium species, i.e., attachment of the (Mc2NC=NMe2) unit to N3 of 7-azabenzotriazole 1-A-oxide instead of to the O, is based on X-ray analysis (ref. 33b)]. 

In addition to the more or less popular methods of depsipeptide synthesis discussed vide supra, there are also a limited number of complementary and effective synthetic procedures that have been described for this purpose. Among these, the well-known method of symmetric anhydrides from N-protected amino acids has to be considered. This method has found successful use in the esterification of hydroxy acids in the presence of some catalyst additives. Initially, the addition of pyridine11091 or 1-hydroxybenzotriazole in pyridine1 101 to a symmetric anhydride was utilized for ester bond formation. As an example, Katakai has prepared a number of didepsipeptides in 85-96% yield by means of a 2-nitrophenylsulfenyl /V-carboxy anhydride with lactic acid derivatives in the presence of pyridine.1 09 ... 

The electron-withdrawing effect of the pyridine nucleus is very substantial, as evidenced by comparisons of the pK of the benzo-fused systems versus the pyridyl-fused systems. For example, the pK of benzotriazole (4) and triazolo[4,5-6]pyridine (5a) (in 80% aqueous 2-methoxyethanol) are 9.36 and 7.44, respectively <75HCA1521>. Similarly, the pKa for V-hydroxybenzotriazole (10), 3-hydroxytriazolo[4,5-Z ]pyridine (11), and l-hydroxytriazolo[4,5-Z ]pyridine (12) are 4.60, 3.28, and 3.02, respectively <76KGS1418>. 

AD-mix-P 9-BBN Bn Boc Bz BOM CDI m-CPBA CSA Cy DBU DDQ DEAD DIAD DIBAL-H DIPT DME DMF DMAP DMSO EDC HMPA HOBT KHMDS LDA MEM MOM MoOPH NaHMDS NBS NMM NMO Piv PMB Reagent for Sharpless asymmetric dihydroxylation 9-Borabicyclo[3.3.1 ]nonyl Benzyl t-Butoxy carbonyl Benzoyl B enzyloxy methyl Carbonyldiimidazole m-Chloroperoxybenzoic acid Camphorsulfonic acid Cyclohexyl 1,8 -Diazabicy clo[5.4.0] undec-7-ene 2,3 -Dichloro-5,6-dicyano-p-benzoquinone Diethyl azodicarboxylate Diisopropyl azodicarboxylate Diisobutylaluminum hydride Diisopropyl tartrate Dimethoxyethane A,N-Dimethylformamide 4-Dimethylaminopyridine Dimethyl sulfoxide N-(3-Dimethylaminopropyl)-A -ethylcarbodiimide Hexamethylphosphoramide 1 -Hydroxybenzotriazole Potassium hexamethyldisilazane Lithium diisopropylamide Methoxyethoxymethyl Methoxymethyl Oxidodiperoxymolybdenum(pyridine)(hexamethylphophoramide) Sodium hexamethyldisilazane N - Bromosuccinimide A-Methylmorpholine A-Methylmorpholine A-oxide Pivaloyl /j-Methoxybenzyl... 

Due to its wide application in peptide synthesis, 1-hydroxybenzotriazole 849 is the most commonly used benzo-triazole derivative with hundreds of references in Chemical Abstracts each year. The utility of 849 (Scheme 183) rests essentially on its readiness to form esters with carboxylic acids in the presence of dehydrating agents. l-Hydroxy-7-azabenzotriazole 847 is also used in peptide coupling reactions, especially with sterically encumbered amines. The faster reaction rates and reduced racemization is attributed to base catalysis by the adjacent pyridine nitrogen 848 during the coupling reactions. 

A solution of 80 pi apiece 0.2 M l-methyl-2-pyrrolidinone 2-thiophenecarboxylic acid (Step 5 Acid), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexaflu-orophosphate, 1-hydroxybenzotriazole, 30 pi 0.2 M l-methyl-2-pyrrolidinone, and 0.5 M apiece diisopropylethylamine and pyridine were stirred 30 minutes, then treated with 75 pi 0.2 M l-methyl-2-pyrrolidinone containing the Step 4 product. The mixture was stirred overnight at ambient temperature, then concentrated, and diluted with 1000 pi CH2C12. The solution was washed with 800 pi apiece saturated NaHC03 solution and 1.81% HC1 and then brine. The organic layer was reconcentrated and the product isolated in 51 % yield. 

Synonyms HOAt l-Hydroxy-lH-v-triazolo[4, 5-b]pyridine 7-Aza-l-hydroxybenzotriazole [1,2, 3]Triazolo[4,5-6]pyridin-3-ol 3-Hydroxy-3H-l,2, 3-triazolo[4,5-6]pyridine HATU lH-l,2,3-Triazo-lo [4,5-6]pyridinium, 1 - [bis( dimethylamino)methyl-ene]-, hexafluorophosphate 1-), 3-oxide HATU may crystallize as guanidinimum N-oxides N-form), rather than the isomeric uranium structures (0-form) depending on storage conditions N-[(di-methylamino)-lH-l,2,3-triazolo[4,5-fc]pyridine-l-yl-methylene] -N-methylmethanaminium hexafluorophosphate. PyAOP Tri-l-pyrrolidinyl(3H-... 

Sample preparation 1 mL 1.23 mg/mL ketoprofen in dichloromethane -i 300 p,L 1 mg/mL hydroxybenzotriazole in dichloromethane pyridine 99 1 -1- 300 p,L 11 mg/mL l-ethyl-3-dimethylaminopropylcarbodiimide in dichloromethane + 300 p.L 3.47 mg/mL 1-naphthy-lamine (Caution 1-Naphthylamine in a carcinogen ) in dichloromethane, vortex, let stand for 1 h, evaporate to dryness under a stream of nitrogen, reconstitute with 5 mL MeOH, inject an aliquot. 

N(3)-Hydroxytriazolo[4,5-b]pyridine plOl, HOAt], as its uronium or phosphonium salts, demonstrated superior performance in solid state peptide synthesis as compared to N-hydroxybenzotriazole [102, HOBt]. This feature enhances the automated synthesis of peptides containing hindered amino acids or hindered amines [94CC201]. 

A similar involvement of a nearby N atom must be assumed also in the rapid aminolysis of esters of 5-chloro-8-hydroxyquinoline [30], 2-hydroxy- and 2-mercapto-pyridine [31] and of 1-hydroxybenzotriazole [32] ... 

The sulfonamide-derivatized support is readily prepared by treating amino-methylated resin with 4-carboxybenzenesulfonamide, N,N-diisopropylcarbodi-imide, and 1-hydroxybenzotriazole. Treatment of the sulfonamide resin with pentafluorophenyl active ester of 4-bromophenylacetic acid and 4-(dimethyl-amino) pyridine then gives the acylsulfonamide. Subsequent treatment of acylsulfonamide with excess LDA (15 equiv) in THF at 0 °C results in rapid deprotonation to give the trianion. 

Recently, other uronium salts, such as 0-(Ai-succinimidyl)-MA. Af.A -tetramethyluronium tetrafluoroborate (TSTU)," 0-(iV-5-norbornene-endo-2,3-dicarboximidyl)-AI, N, N, iV -tetra-methyluronium tetrafluoroborate (TMTU)," 0-(2-oxo- (2H)-pyridyl)-AI,AI,iV, Af-bis(pentamethylene)uronium tetrafluoroborate (TOPPipU), N-[(Dimethylamino)-lH-l,2,3-triazolo[4,5-b]pyridin-l-ylmethylene]-N-methylmethanaminium Hexafluorophosphate N-Oxide (HATU), and 0-(7-azabenzotriazol-l-yl)-AI,AI,iV, Af-bis(tetramethylene)uronium hexafluorophosphate (HAPyU) have been described and are commerically available. The uronium salts derived from 7-aza-l-hydroxybenzotriazole (HATU and HAPyU) have been shown to be superior to their benzotriazole analogs in terms of coupling efficiency, racemization, and cyclization, in both solution and solid-phase strategies. 

Related Reagents. 1-Hydroxybenzotriazole iV-Hydroxy-suecinimide Imidazole Pyridine. 

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