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A simple, inexpensive and efficient method for the selective cleavage of N-Boc protecting group under acidic conditions on high load Wang resin is described. This method employs the use of concd sulfuric acid in 1,4-dioxan and provides an efficient process for the complete Boc deprotection with minimal loss of substrate through cleavage from resin. Solid phase organic synthesis (SPOS) has been widely applied for preparing small organic molecule libraries for screening purposes. 1 More recently, the scale-up of a variety of solid phase syntheses using a high load (4 mmol/ g) Merrifield resin has been reported. 2 Consequently, the approach of using high load resins in solid phase chemistry for the preparation of the initial quantities of drug substance required for pre-clinical toxicological studies is now feasible. This not only requires that all steps are chemically efficient (conversion and isolated yield) but also imposes cost limitations on the use of certain reagents.In general, the use of N-Boc protection strategies for solid phase synthesis is currently limited to acid stable resins with the initial step in the synthesis being the direct attachment of substrate to Merrifield resin. However, the forcing conditions required to cleave the product from the resin limits the nature of compounds that can be prepared using this strategy. The alternative approach is to use orthogonal base sensitive protecting groups such as Fmoc in association with modified resins such as Wang and 2-chlorotrityl, which allow the use of milder resin cleavage conditions such as 50% TFA in dichloromethane (DCM). 3,4 However, on larger scales the cost associated with the use of Fmoc protected monomers can become prohibitive. In this letter we describe a simple method of N-Boc deprotection, which is compatible with Wang resin.Recently we wished to prepare the dipeptide (4) and opted to follow a SPOS strategy using high load Merrifield derived Wang resin, Scheme 1. Although there are a number of methods available for N-Boc deprotection on solid support, 5 including the use of TMSOTf/Lutidine, 6 TMSCl/ Phenol, 7 , silicon tetrachloride, 8,9 aluminium chloride 10 and dilute aqueous HCl in organic solvents, 11,12 we encountered difficulties in the selective removal of a N-Boc group without appreciable loss of substrate through cleavage from the resin. For example, using TMSOTf/2,6-lutidine, at least two treatments with fresh reagents were necessary and even then the reaction was incomplete giving rise to other unidentified impurities. Similarly, whilst the use of TMSCl/Phenol for the selective removal of the Boc protection appeared to work well on small scale (1-5g), the results were inconsistent and at times gave as much as 20-25% loss of product from cleavage of the resin. Attempts to enhance this protocol through the use of fresh TMSCl (to minimise the presence of residual HCl) or TMSCl pre-treated with sodium carbonate and high purity phenol (>99%) failed to give more consistent results. Furthermore, attempts to increase selectivity by u...

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This work describes the use of electrochemical impedance spectroscopy (EIS) as a means to monitor solid phase synthesis on resin beads. EIS was used to track changes during the swelling of beads in various solvents, during three typical reactions and throughout cleavage of the final product from the bead. The impedance response was investigated in a chemical reactor and was found to be faintly sensitive to the resin swelling and solvent flow. The position of the electrode within the reactor was found to be critical as polystyrene based beads float or sink dependent upon the solvent used. However, by choosing electrode position it was possible to monitor reaction progress on beads or within the bulk reactant/product mixture. Of the three typical chemical reactions studied impedance spectroscopy successfully followed two. Fitting of the impedance data to an equivalent electrical circuit provided an estimate as to the relative contribution of capacitive and resistive components to the overall response. Kinetic data from two reactions were also modelled, in both cases complex kinetics was observed, in close agreement with other studies.

The efficient synthesis of rigid multifunctional vinylic monomers 1 and 2 from 3,5-dibromobenzene derivatives and propargyl alcohol via the Sonogashira reaction is reported. For example, a series of 3,5-bis(3-hydroxyprop-1-ynl)benzoate ester derivatives have been prepared efficiently using an improved palladium catalyst system. Subsequent hydrolysis and reaction with 4-vinylaniline afforded a new monomer 2 for use in functional macroporous polymer systems. In addition, Sonogashira and Wittig methodologies have been optimised in order to construct successfully an alternative rigid monomer 1 from 3,5-dibromobenzaldehyde.The palladium(0)/copper(I) halide catalysed coupling of terminal alkynes with aryl or alkenyl halides, first reported 1 by Sonogashira and co-workers, is a widely used method for the synthesis of arylalkynes and conjugated enynes. 2 As part of our research towards the synthesis of novel rigid vinylic monomers 1 and 2 ( Figure) for use in imprinted polymer systems, 3 an efficient and robust procedure for the coupling of propargyl alcohol to a range of 3,5-dibromobenzene derivatives was required. Consequently, use of Sonogashira coupling methodologies was investigated and the results of these studies are reported herein.The synthesis of monomer 1 employed the conditions reported 4 by Brown et al. for the synthesis of 3,5-dibromobenzaldehyde from 3,5-dibromobenzoic acid via a two step reduction/selective oxidation process (Scheme 1). Employing the original reaction conditions described 1 by Sonogashira and co-workers (0.4 mol% Pd (PPh 3 ) 2 Cl 2 , 0.8 mol% CuI, triethylamine, THF) in conjunction with 3,5-dibromobenzaldehyde and propargyl alcohol, the key intermediate 3,5-bis(3-hydroxyprop-1-yl)benzaldehyde 3 was constructed in good yield (Table, entry 1). The hydroxyl moieties of 3 were then protected in the form of their corresponding tert-butyldimethylsilyl (TBDMS) ethers. Subsequent conversion of the aldehyde group of the protected diol 4 to the corresponding olefin 5 employing standard Wittig conditions 5 followed by deprotection of the TBDMS groups afforded the desired monomer 1 in 96% yield.In addition to monomer 1, novel rigid monomers such as 2 ( Figure), comprised of 3,5-bis-acetylenated aromatic units tethered to a polymerisable vinylic group, were also targeted to enable structure-property relationships of the resultant imprinted polymers to be studied. The approach used to obtain monomers such as 2 also involved use of the palladium mediated cross-couplings of propargyl alcohol to 3,5-dibromobenzoic acid ethyl ester (Scheme 2). However, in stark contrast to monomer 1, the synthesis of monomer 2 required significant modification of the Sonogashira-based methodologies.Under the original coupling conditions (Table, entry 2), the desired bis-acetylenic product 6a was not isolated, only a moderate yield of mono-substituted product 7a was obtained. This effect has also been observed 6 by Krause and co-workers in the coupling of trimethylsilylacetylene to methyl bromobenzoate derivatives and highe...