Imine support-bound

One of the most convenient preparations of alkylamines on insoluble supports is the reduction of imines, which can readily be prepared from either support-bound amines or support-bound carbonyl compounds (Figure 10.3). 

Nucleophiles other than hydride can be added to support-bound imines to yield amines. These include C,H-acidic compounds, alkynes, electron-rich heterocycles, organometallic compounds, boronic acids, and ketene acetals (Table 10.9). When basic reaction conditions are used, stoichiometric amounts of the imine must be prepared on the support (Entries 1-3, Table 10.9). Alternatively, if the carbon nucleophile is stable under acidic conditions, imines or iminium salts might be generated in situ, as, for instance, in the Mannich reaction. Few examples have been reported of Mannich reactions on insoluble supports, and most of these have been based on alkynes as C-nucleophiles. 

Support-bound C-nucleophiles have also been successfully added to imines. Poly-styrene-bound thiol esters can be converted into ketene acetals by O-silylation, and then alkylated with imines in the presence of Lewis acids. Further examples include Mannich reactions of support-bound alkynes and indoles (Table 10.10). Some Man-nich-type products (e.g. 3-(aminomethyl)indoles, 2-(aminomethyl)phenols, (3-amino ketones) are unstable and can decompose upon treatment with acids. 3-(Amino-... 

Table 10.9. Addition of C-nucleophiles to support-bound imines and hemiaminals.

Table 10.10. Addition of support-bound C-nucleophiles to imines.

Several types of imine have been used as protective groups for amines in solution [230]. Most are stable towards bases, but can be hydrolyzed by acids. Benzophenone-derived imines can be prepared by treating support-bound aliphatic primary amines with benzophenone imine [148,260], but usually not by treatment with benzophenone. Polystyrene-bound benzophenone imines of glycine are sufficiently C,H-acidic to enable C-alkylation with alkyl halides [260,313] or Michael acceptors [314], and have mainly been used for this purpose (see Section 13.4.4). 

Phosphonates react with aldehydes or imines to yield a-hydroxy- or a-aminoalk-ylphosphonates, respectively. These reactions can also be conducted on cross-linked polystyrene. In Figure 11.2, a sequence is outlined in which polystyrene-bound H-phosphonates are treated with imines and aldehydes. The variant in which a support-bound imine is converted into an a-aminoalkylphosphonate has also been reported... 

Sulfonyl chlorides possessing an a-hydrogen undergo elimination of hydrogen chloride when treated with bases to yield sulfenes. Like ketenes, sulfenes can undergo [2 + 2] cycloaddition to support-bound imines to yield p-sultams (Entry 5, Table 15.2). 

Thiazolidin-4-ones have been prepared by condensation of support-bound imines with a-mercapto carboxylic acids (Entry 11, Table 15.18). These thioaminals are quite stable and tolerate, for example, treatment with TFA [228,229]. Thiazolidines, which can be prepared from resin-bound cysteine and aldehydes (Entry 12, Table 15.18), are also remarkably stable towards acid-promoted hydrolysis. Libraries of thiazolidinones have been used to identify new cyclooxygenase-1 inhibitors [230]. 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

A new solid-phase technique used a relatively nontoxic cleaving agent for peptide aldehydes, which would prevent lithium aluminum hydride reduction byproduct contamination 51 A support-bound threonine or serine was treated with the substrate aldehyde to give an imine intermediate that immediately cyclized to give the stable oxazolidine linker, which was stable to Fmoc conditions including treatment with TFA. The peptide was cleaved under mild aqueous conditions at 60 °C 51 ... 

The most common C-X fragments are imines, which can be readily obtained from a polymeric support aldehyde by many high-yielding methods [281, 282, 283]. Dor-wald et al. reported Wang resin-supported 3-enaminoamides [284]. Yamazaki generated enamines from support-bound phosphonoesters [148]. Imines serve as starting materials for [2 -r 2]-cycloadditions, [2 -i- 3]-dipolar cycloadditions, and het-ero Diels-Alder reactions (HD). 

Isomannide (80) was the core for a hexahydrofurofuran library." Primary amines were loaded onto solid-support by reductive amination and acylated with bromoacetic acid to give bromides 79 (Scheme 7.16). Alkylation of bromides 79 on solid-support with isomannide (80) gave the solid-supported alcohols 81. A Mitsunobu reaction with phthalimide (82) proceeded to furnish amines 83 in excellent yield and purity after removal of the protecting group." " Support-bound primary amines 83 were converted to secondary amines by stepwise imine formation with aldehydes 84 and reduction with sodium borohydride." The hindered secondary amines 85 were acylated with acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates to yield 87 after cleavage from solid-support. 

Resin-bound 7-keto sulfones, prepared in a straightforward, three-step process comprising alkylation of a resin-bound sulfinate salt, alkylation of a sulfone-supported anion with an epoxide, and Jones oxidation of the 7-hydroxy sulfone, provided a source of structurally diverse three-carbon fragments <2004JC0928>. Reaction with a phenylenediamine to give the 1,5-benzodiazepine presumably occurs via initial imine formation followed by expulsion of the resin-bound sulfone, which acts as a traceless linker (Scheme 73). Yields for this process are a modest 10-38%. 

Polymer-bound P-lactams have been prepared via the ester enolate imine condensation route <02JOC8034>. On the other hand, an efficient asymmetric synthesis of 2-azetidinones was accomplished when chiral acid chlorides or chiral aldehydes were used in the polymer-supported Staudinger reaction <02TA905>. 

At a loading as low as 1 mol%, 10b promoted the hydrocyanation of A-allyl or -benzyl imines derived from aromatic and aliphatic aldehydes and of some ketones in very high yield and almost complete stereoselectivity (see Scheme 2). It is interesting to note that the soluble and the resin-bound catalysts performed equally well. Recovery and recycling of the supported catalyst was shown to occur without any erosion of chemical or stereochemical efficiency over ten reaction cycles. 

Recently, various scavenger resin approaches have appeared in the literature. For the synthesis of 4000 ureas (400 pools of 10-compound mixtures) [47], a solid-supported amino nucleophile was used to quench the excess of isocyanates, yielding the desired products in good purity. A similar concept has been employed in the synthesis of 2-thioxo-4-dihydropyrimidinones using aminomethylated polystyrene beads to quench isothiocyanates as well as aldehydes [48]. To quench an excess of amine in the synthesis of 2,6,9-trisubstituted purines, formyl polystyrene beads were used to form the corresponding polymer-bound imine, which could be filtered off [49]. 

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