Polymer-supported aldehyde

Synthesis of f-lactams from support-hound imines (Scheme 50) [191] To polymer-supported aldehyde (227) (0.64 mmol g 200 mg, 0.13 mmol) preswollen in CH2CI2 were added 4 A MS and benzylamine (85 pL, 0.77 mmol) in anhydrous CH2CI2 (3 mL). The resin was shaken for 30 min then drained. 

Zhu and coworkers have reported the synthesis of functionalized poly(vinyl alcohol) resins for use as scavengers [13]. This was achieved via inverse suspension polymerization along side epichlorohydrin as a cross-linker. These resins were found to have excellent swelling characteristics in DMF, CH3OH, dioxane, THF, CH2C12 and H20. These were then functionalized with glutaric aldehyde to provide a polymer-supported aldehyde (Scheme 8.8). 

This polymer-supported aldehyde was found to scavenge both alkyl as well as aryl primary amines over secondary amines and exhibit remarkable facility in the synthesis of a demonstration library of amides, ureas and secondary amines (Scheme 8.9). 

Figure 14.15 Immobilization ofdiols using polymer-supported aldehydes.

Reggelin and Brenig reported a different approach for the asymmetric synthesis on solid support (Scheme 1.6.38). An acylated Evans auxiliary was used as a soluble reagent for the transformation of polymer-supported aldehyde 81 into imide 82. The latter was converted into the Weinreb amide 83 which was - after protection of the hydroxyl group - submitted to DIBAH reduction to generate aldehyde 84. 

As shown in Scheme 4.3.4, several substituted hydroxybenzaldehydes 226 were attached to Wang resin 84 via an alkylaryl ether linkage through a Mitsunobu reaction to give 227. These polymer-supported aldehydes were allowed to react with an a-amino ester 228 and maleimide 229 in DMF to give immobilised proline analogues 230 that were liberated from the resin by treatment with 50% TFA to afford 231. The dipolar cycloaddition provided mixtures of diastereoisomers, which could be separated by HPLC. 

Interestingly, it took almost 8 years when the next solid-phase allylation reaction was reported again using a chiral silane. Tan and coworkers reported the asymmetric allylation of an aliphatic polymer-supported aldehyde using a strained aUylsilacycle 24 developed by Leighton and coworkers (Scheme 7.4b). The homoallylic alcohol 25 was obtained in good enantiopurity and yields. 

The use of an acidic solution of p-anisaldehyde in ethanol to detect aldehyde functionalities on polystyrene polymer supports has been reported (beads are treated with a freshly made solution of p-anisaldehyde (2.55 mL), ethanol (88 mL), sulfuric acid (9 mL), acetic acid (1 mL) and heated at 110°C for 4 min). The colour of the beads depends on the percentage of CHO content such that at 0% of CHO groups, the beads are colourless, -50% CHO content, the beads appear red and at 98% CHO the beads appear burgundy [Vdzquez and Albericio Tetrahedron Lett 42 6691 200]]. A different approach utilises 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (Purpald) as the visualizing agent for CHO groups. Resins containing aldehyde functionalities turn dark brown to purple after a 5 min reaction followed by a 10 minute air oxidation [Coumoyer et al. J Comb Chem 4 120 2002]. 

Polymer-supported amino alcohols and quaternary ammonium salts catalyze the enan-tioselective addition of dialkylzinc reagents to aldehydes (Table 31). When the quaternary ammonium salt F is used in hexane, it is in the solid state, and it catalyzes the alkylation of benzaldehyde with diethylzinc in good chemical yield and moderate enantioselectivity. On the other hand, when a mixture of dimethylformamide and hexane is used as solvent, the ammonium salt is soluble and no enantioselectivity is observed21. 

A novel and versatile method for preparing polymer-supported reactive dienes was recently developed by Smith [26]. PS-DES (polystyrene diethyl-silane) resin 28 treated with trifluoromethanesulfonic acid was converted to a polymer-supported silyl triflate 29 and then functionalized with enolizable a,jS-unsaturated aldehydes and ketones to form silyloxydienes 30 and 31 (Scheme 4.4). These reactive dienes were then trapped with dienophiles and the Diels Alder adducts were electrophilically cleaved with a solution of TFA. 

The N-substituted aminoacids required could be prepared by microwave-assisted reductive amination of aminoacid methyl esters with aldehydes, and although in the Westman report soluble NaBH(OAc)3 was used to perform this step, other reports have shown how this transformation can be performed in using polymer-supported borohydrides (such as polymer-supported cyanoborohydride) under microwave irradiation [90]. An additional point of diversity could be inserted by use of a palladium-catalyzed reaction if suitably substituted aldehydes had been used. Again, these transformations might eventually be accomplished using supported palladium catalysts under microwave irradiation, as reported by several groups [91-93]. 

A polymer-supported version of our optimal ligand was also developed [52]. Its preparation involves attachment of aziridine carbinols to polymer-bound triphenylchloromethane (Scheme 40). This polymer-bound ligand 53 was almost equally effective in the enantioselective addition of diethylzinc to aromatic and aliphatic aldehydes with ee s ranging from 77-97% for the latter type of substrate [52]. It is of practical interest that this polymer-supported ligand could be reused without losing much of its efficiency. 

Leznoff CC, Wong JY. The use of polymer supports in organic synthesis. III. Selective chemical reactions on one aldehyde group of symmetrical aldehydes. Can J Chem 1973, 51 3756-3764. 

Devaky and Rajasree have reported the production of a polymer-bound ethylenediamine-borane reagent (63) (Fig. 41) for use as a reducing agent for the reduction of aldehydes.87 The polymeric reagent was derived from a Merrifield resin and a 1,6-hexanediol diacrylate-cross-linked polystyrene resin (HDODA-PS). The borane reagent was incorporated in the polymer support by complexation with sodium borohydride. When this reducing agent was used in the competitive reduction of a 1 1 molar mixture of benzaldehyde and acetophenone, benzaldehyde was found to be selectively reduced to benzyl alcohol. 

In 2001, Sarko and coworkers disclosed the synthesis of an 800-membered solution-phase library of substituted prolines based on multicomponent chemistry (Scheme 6.187) [349]. The process involved microwave irradiation of an a-amino ester with 1.1 equivalents of an aldehyde in 1,2-dichloroethane or N,N-dimethyl-formamide at 180 °C for 2 min. After cooling, 0.8 equivalents of a maleimide dipo-larophile was added to the solution of the imine, and the mixture was subjected to microwave irradiation at 180 °C for a further 5 min. This produced the desired products in good yields and purities, as determined by HPLC, after scavenging excess aldehyde with polymer-supported sulfonylhydrazide resin. Analysis of each compound by LC-MS verified its purity and identity, thus indicating that a high quality library had been produced. 

A variation of this method led to the generation of bis-benzimidazoles [81, 82], The versatile immobilized ortho-phenylenediamine template was prepared as described above in several microwave-mediated steps. Additional N-acylation exclusively at the primary aromatic amine moiety was achieved utilizing the initially used 4-fluoro-3-nitrobenzoic acid at room temperature (Scheme 7.72). Various amines were used to introduce diversity through nucleophilic aromatic substitution. Cyclization to the polymer-bound benzimidazole was achieved by refluxing for several hours in a mixture of trifluoroacetic acid and chloroform. Individual steps at ambient temperature for selective reduction, cyclization with several aldehydes, and final detachment from the polymer support were necessary in order to obtain the desired bis-benzimidazoles. A set of 13 examples was prepared in high yields and good purities [81]. 

The synthesis of 4,5-disubstituted triazoles shown in Scheme 208, carried out on a polymer support with microwave assistance, is based on a similar principle. In the first step, sulfinate 1248 is converted to sulfone 1249. Condensation with aldehydes provides vinyl sulfones 1250. Cyclocondensation of sulfones 1250 with sodium azide generates corresponding triazoline intermediates that eliminate sulfinate 1248 to provide triazoles 1251 in moderate to good yield <2006OL3283>. 

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