Benzotriazoles 1-hydroxybenzotriazole

Few reports describe reactions of substituents at the benzene ring of benzotriazoles. The facile deprotonation of the methyl group in N-Boc-7-methyl-1-aminobenzotriazole (403) with butyllithium followed by reactions with electrophiles gives substituted products (404) (Scheme 78). The electrophile can be an alkyl halide, an aldehyde or a ketone, and the Boc group is removed by brief exposure to CF3CO2H in CH2CI2 <93TL6935>. 1-Acetylbenzotriazole (405) is hydrolyzed to form 3-(177-5-hydroxybenzotriazol-6-yl)propionic acid (406), which is then converted (Scheme 79) to... 

Oxidation of 1-hydroxybenzotriazole (446) in the absence of oxygen gave the benzotriazole 1-oxide radical (447), which, on reaction with DMAD, evolved nitrogen and formed the new radical 448.235... 

Abbreviations DCM, dichloromethane DIC, 1,3-diisopropylcarbodiimide DIEA, diiso-propylethylamine DMAP, 4-dimethylaminopyridine DMF, IVJV-dimethylformamide ELSD, evaporative light scattering detection HOBt, hydroxybenzotriazole IR, infrared LC/MS, high-pressure liquid chromatography/mass spectrometry NMM, V-methylmorpho-line NMR, nuclear magnetic resonance PyBop, benzotriazol-l-yloxytripyrrolidino-phosphonium hexafluorophosphate SAR, structure-activity relationship TFP, tetrafluorophenol THF, tetrahydrofuran. 

Abbreviations BOP, benzotriazol-l-yloxy-tris(dunethylamino)phosphonium hexafluoro-phosphate DCC, N.N -dicyclohexylcarbodiimide DIC, /V./V -diisopropylcarbodiimide DME, dimethoxyethane DMF, /V./V-dimethyl form amide DIEA, /V-cthyldiisopropyla-mine Et20, diethyl ether HOBt, 1-hydroxybenzotriazole HOSu, iV-hydroxysuccimmide t-BuOMe, tert-butylmethylether TFA, trifluoroacetic acid TIS, triisopropylsilane. 

Peptide synthesis reagents such as diisopropylcarbodiimide (DIC), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP), 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1-hydroxybenzotriazole (FlOBt), piperidine, A-methylmorpholine (NMM), trifluoroacetic acid (TEA), triisopropylsilane (TIS), A -diisopropylethylamine (DIPEA, DIEA), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,2-ethanedithiol (EDT), and 4-dimethylaminopyridine (DMAP) may be obtained from Sigma-Aldrich, Chemlmpex, and Novabiochem. 

The reactivity of substituents attached to ring carbon atoms is of much interest, mainly when it concerns complex fused-ring thietanes linked to naturally occurring compounds. The representative example of such a case is conversion of the thymine-thietane derivative 55 to its flavin derivative 56 in the presence of 1-hydroxybenzotriazole (HOBT) and 2-(l -benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) (Equation 12) <20050BC1937>. 

SCHEME 11.4 Convergent concept demonstrated by the Lansbury group. Bn, benzyl cHex, cyclohexyl DIPEA, diisopropylethylamine DMSO, dimethyl sulfoxide DNP, 2,4-dinitrophenyl HBTU, 2-(l//-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate HOBt, 1-hydroxybenzotriazole Ts, tosyl. 

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>. 

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. 

Hydroxybenzotriazole (HOBt) and 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyl-ammonium tetrafluoroborate (TBTU). 

Abbreviations used Dde, N-[l-(4,4-dimethyl-2,6-dioxocyclohexadiene)]-ethyl DIEA, diisopropylethylamine DMF, N,N-dimethylformamide EDC, l-Ethyl-3-(3 -dimethylaminopropyl)carbodiimide hydrochloride HOBt, 1-hydroxybenzotriazole NHS, N-hydroxysuccinimide NMP, l-methyl-2-pyrroIidinone PAL, Peptide Amide Linker [5-(4-(9-fluorenylmethyloxycarbonyl) aminomethyl-3,5-dimethoxyphenoxy) valeric acid] PyBOP, Benzotriazole-l-yl-oxy-trispyrrolidino-phosphonium hexafluorophosphate TFA, trifluoroacetic acid. 

Abbreviations Boc f-butyloxycarbonyl BOP benzotriazole-1-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate BuVfBu f-butyl DIEA diisopropylethylamine DMF N,N-dimethylformamide DAST diethylaminosulfur trifluoride Fmoc 9-fluorenylmethoxycarbonyl HATU 0-(7-azabenzotriazol-1-yl)-1,3,3-tetramethyluronium hexafluorophosphate HOBt hydroxybenzotriazole NMM 4-methylmorpholine Pbf 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl PEG-PS polyethylene glycol-polystyrene TFA tiifluoroaceticacld Trt tiityl. 

For both the preliminary and fined test peptides, it was necessary to prepare all possible isomers as standards for analysis. These reference peptides were synthesized using a PE-ABD 430A peptide synthesizer configured for FastMoc synthesis protocols. Piperidine (20%) in N-methylpyrrolidone (NMP) was used to deprotect the N-terminal amino acid. To activate each amino acid in the reaction vessel, the following was used 1.0 mM amino acid, 1.0 mM 2-(lH-benzotriazol-l-yl)-l-l-2,3, tetramethyluronium hexafluorophosphate (HBTU) in 1 M 1-hydroxybenzotriazole (HOBT) in NMP, 2.0 mM diisopropylethylamine (DIEA). Each His residue was double-coupled. HBTU, DIEA, piperidine, DMF and NMP were purchased from ABI. Methylene chloride was purchased from Burdick and Jackson. 

SCHEME 10. Synthesis of H2N-(Thr)2-(LacNAc-a-Thr)-(Thr)2-Gly-OH. Conditions (i) H2, Pd(C), MeOH-AcOH (10 1), 1 h (ii) 20% piperidine in DMF (iii) Fmoc-Thr, (benzotriazol-l-yloxy)tripyrrolidi-nophosphonium hexafluorophosphate (PyBOP), IV-hydroxybenzotriazole (HOBt), ethyldiisopropylamine (DIPEA) (iv) Glyco-amino acid 64, PyBOP, HOBt, DIPEA (v) TFA (vi) NaOMe, MeOH. 

The dielectric strength of polyethylene has been measured as a function of additive concentration while in stabilised polymers the depth of degradation was found to be uniform . HALS have been found to be effective stabilisers for UV cured coatings and do not influence the cure rate . Bleached wood pulps can be effectively stabilised by ascorbic acid and wool by hydroxy-benzotriazoles and HALS . Hydroxybenzotriazole stabilisers also protect wood pulp and polyurethanes by co-reaction . The spectroscopic properties of monomeric and polymeric benzotriazoles have also been compared . UV absorbers are effective in clear coats and when grafted to wood . Dihydroxybenzophenone stabilisers inhibit the chain scission in the photodegradation of poly(methoxyacrylophenone) while tin stabilisers have also been found to photostabilise PVC . 

---