Benzotriazole linkers

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]. 

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Benzotriazole Linker Units. The final class of nitrogen-based linker units... 

Another example for a N-containing linker system is the benzotriazole hnker that can be generated by several ways of attaching benzotriazole to sohd supports [258,259]. This hnker is often used for the synthesis of amine hbraries (Scheme 53). Therefore the benzotriazole linker 371 is reacted with aldehydes 372 and amines 373 to form Mannich-type adducts 374 which can be detached from the resin either by Grignard or zinc reagents or under reductive conditions using sodiiun borohydride [260]. 

Traceless linker 60 based on a benzotriazole scaffold was reacted with amines and aldehydes to produce Mannich-type amine products [69]. Final product release was achieved by treatment with Grignard reagents (Scheme 29). 

Schiemann K, Showalter HDH. Development of polymer-supported benzotriazole as a novel traceless linker for solid-phase organic synthesis. J Org Chem 1999 64 4972 1975. 

T1 resin traceless linker [131-134], synthesis of phenols [135], biaryls, alkyl arenes [136, 137], azides [138], aromatic hydrazines, halides [cf. 128, 129, 139], ester, azo compounds, cinno-lines [140], benzotriazoles [141]... 

Recently, three research groups independently disclosed that benzotriazoles 18 attached through various linkers to a polymeric support react with aldehydes and amines to form polymer-anchored Mannich-type adducts 19 (Scheme 7) [29]. These intermediates are cleaved under reducing conditions and in the presence of organomagnesium or organozinc reagents to provide libraries of secondary and tertiary amines in moderate yield (11-65%) and with acceptable purity (13->99%) [29]. 

Paio A, Crespo RF, Seneci P, Ciraco M, Solid-supported benzotriazoles. 2. Synthetic auxiliaries and traceless linkers for the combinatorial synthesis of unsymmetrical ureas, J. Comb. Chem., 3 354-359, 2001. 

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. 

The T1 linker system has been successfully apphed to solid-phase syntheses of 3-lactams [136] and of substituted IH-benzotriazoles [156]. Improvements with... 

Chitosan, derived from crab shell chitin, is —80% deacetylated. It is dissolved in 1 M HO Ac (5 g/L) and freeze dried to yield a white, soft material. The chitosan is washed with 0.9 M A-methylmorpholine (NMM) in DMF followed by DMF. The Rink linker (0.4 mmol) is dissolved in 6 mL of DMF containing N-[(17/-benzotriazol-1 -yl)(dimethylamino)methylene]-A-methyl-methanaminium tetrafluoroborate A-oxide (TBTU) (0.3 M), HOBt (0.3 M), and NMM (0.4 M) and added to 150 mg (dry weight) of chitosan. The mixture is incubated at 45°C for 1 h, washed with DMF, and the chitosan capped with acetic anhydride-dry pyridine (1 1, v/v) for 1 h at 45°C. This procedure yields Fmoc-linker substituted chitin (Fig. 16). After drying in vacuo, the degree of substitution is determined by measuring the Fmoc released after treatment of a sample with piperidine-DMF (3 7) for 30 min at room temperature. Typically, chitosan substitution levels are 0.08-0.35 mmol/g. 

However, due to the fact that the strategy outlined in Scheme 47 is limited to the generation of 5-nitro-substituted benzotriazoles 332, a different access to o-amino-substituted triazenes was sought. Starting from o-nitro triazenes 335, reduction under newly developed conditions (Zimmermann et aL, 2007, personal communication) suitable for acid sensitive linkers gave access to the o-amino-substituted resins. Consequently, a reductive-amination strategy was also viable, fii this case, 3-alkylmethyl or 3-arylmethyl benzotriazoles 338 are accessible in good yields (Scheme 48). 

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