Piperazino-functionalized silica gel as a deblocking-scavenging agent for the 9-fluorenylmethyloxycarbonyl amino-protecting group

Abstract

Bonding cyclic secondary amino residues to the surface of silica gel has given insoluble reagents capable of deblocking the 9-fluorenylmethyloxycarbonyl amino-protecting group and at the same time scavenging the dibenzofulvene (DBF) liberated in the deblocking process. A piperazino silica reagent 6 bearing approximately 1.1 mequiv of NH/g was easiest to prepare by reaction of trimethoxysilane 5 with chromatographic-grade silica.After use, spent reagent could be regenerated by treatment with excess piperidine. Piperidino silicas 14 and 15 were made similarly. For the amino-functionalized silica reagents and a variety of simple cyclic secondary amines (piperazine, piperidine, etc.) the existence of an equilibrium (eq 3) between DBF (2) and adduct 7 has been established with the position of equilibrium being dependent on the nature of the amine, solvent, etc. Both deblocking and attainment of equilibrium were faster in MezSO than in chloroform or dichloromethane. With piperazines in MezSO the equilibrium was shifted toward complete scavenging by precipitation of the adduct from the reaction medium.Previously' we showed that cross-linked polystyrenes bearing cyclic secondary amino functions of general structure 1 caused deblocking of the 9-fluorenylmethyloxycarbonyl (Fmoc) amino-protecting group2 with the liberation of dibenzofulvene (DBF) 2 which is subsequently scavenged by the same insoluble reagent to give adduct 3 (eq 1). Filtration and evaporation of the solvent then " 3COYHR Q q H -u 1 1 + CO, + RNH, -CHZ 2 3gave only the desired amine. Without removal of 2 the workup is often complicated by its gradual polymerization.In the earliest studies satisfactory reagents of this type were prepared from commercial samples of polystyrene of both microreticular (Dow Chemical Co., 1-2% DVB) and macroreticular (Rohm and Haas Co., XE-305) polystyrenes. Samples of reagent 1 made from polystyrenes obtained more recently from the same suppliers proved satisfactory only for the first step.3 (1) Carpino, L. A.; Williams, J. R.; bpusinski, A. J. Chem. Soc., Chem. (3) Carpino, L. A.; Mansour, E. M. E.; Cheng, C. H.; Williams, J. R.; MacDonald, R.; Knapczyk, J.; Carman, M.; Lopusidski, A. J. Org. Chem., accompanying paper in this issue. 0022-326318311948-0666$01.50/0In view of these difficulties and in anticipation of carrying out such deblocking-scavenging reactions by column rather than batch techniques, we have now investigated analogous nonswelling silica-based reagent^.^ In fact, piperazino-functionalized silica gels proved to be superior to the polystyrene-based reagents. Since they are also far simpler to prepare, they are clearly reagents of choice for synthetic purposes. (Chloropropy1)trimethoxysilane (4) /7 5 0 2 V N n h U (MeO),Si(CH,I,CI -(MeO),Si(CHz13N wNH -5 4~k~s~-(c~2)3~uNH n ( 2) 6 was treated with excess piperazine and the resulting piperazino silane 5 used to bond the appropriate functional group to the surface of activated silica. For the resultant functionalized silica gel 6 loadings of about 1.1 mequiv of act...

New π‐stacked benzofulvene polymer showing thermoreversible polymerization: Studies in macromolecular and aggregate structures and polymerization mechanism

“…The attempts aimed at the isolation of these new compounds failed because 1 was regenerated instead. Therefore, we investigated the formation of these compounds by 1 H NMR spectroscopy (see the Experimental section), and we noted the presence of an equilibrium between 1 , NMP, and the apparently unstable Michael‐type adducts 5 and 6 (Scheme ) analogous to that described for dibenzofulvene 9, 10. However, under the aforementioned experimental conditions, the amount of 1 was substantial, and the depression of the polymerization can be considered an interesting proof of the proposed mechanism.…”

Amino Acid-Protecting Groups

“…piperazine, piperidine) in organic solvents. 53,54 Applied for the first time for SPPS by two different laboratories independently. 55,56 Since then, several optimized removal conditions for SPS have been described, the most relevant being: 20% piperidine in DMF, 55 which is the most common, 1-5% DBU in DMF, 57,58 morpholine-DMF (1:1) 59 or 2% HOBt, 2% hexamethyleneimine, 25% N-methylpyrrolidine in DMSO-NMP (1:1), 60 Fmoc α-amino protection has been used for the SPS of several relevant peptides using the so-called Fmoc/ t Bu strategy, the production in Tm scale of the T20 peptide being one of the most important examples.…”

The immobilization of 3-(chloropropyl)triethoxysilane onto silica by a simple one-pot synthesis

“…Bae et al reported [6] that the reaction needs to be refluxed in toluene for 12 h. The silica can also be functionalized by refluxing in toluene for 24 h. This was followed by soxhlet extraction [9,10] with different organic solvents. Several other researchers had reported the functionalization of silica (which was pre-dried at 100 • C at 2 mm Hg for 6 h) by refluxing it with CPTES in toluene [11] for 18 h. Paul et al [3] showed that 3-(chloropropyl)trimethoxysilane * Corresponding author. Fax: +60 4 6574854.…”