A Solid‐Supported Organocatalyst for Highly Stereoselective, Batch, and Continuous‐Flow Mannich Reactions

Abstract

The fast and highly stereoselective Mannich reaction of aldehydes and ketones with the N-(p-methoxyphenyl) ethyl glyoxylate imine catalyzed by polystyrene resins functionalized with (2S,4R)-hydroxyproline is reported. The effect of the nature of the linker connecting proline with the polymeric backbone has been studied, and a 1,2,3-triazole linker constructed from azidomethyl polystyrene and O-propargyl hydroxyproline turns out to be optimal for catalytic activity and enantioselectivity. With aldehyde donors, fast reactions leading to complete conversion in 1-3 h are recorded in DMF. With ketone donors, the reactions tend to be slower, but can be efficiently accelerated (six-membered ring cycloalkanones) by low-power microwave irradiation. This approach, which greatly facilitates product isolation since the catalyst is removed by simple filtration, has allowed the implementation of the reactions of aldehyde substrates in a continuous-flow, single-pass system. In this manner, the continuous synthesis of the enantiomerically and diastereomerically pure adducts (syn/anti>97:3; ee>99 %) has been achieved at room temperature with residence times of 6.0 min. This methodology has allowed for the preparation of up to 7.8 mmol of the desired Mannich adduct through the use of 0.46 mmol of catalytic resin (5.9 mol %), in a greatly simplified experimental protocol that avoids purification steps.

Ten key issues in modern flow chemistry

“…33 In one example, the authors filled a jacketed omnifit column with the polystyrenesupported proline derivative 39 and introduced it into a flow system. 34 The stereoselectivity of the Mannich-type aldol reaction of propanal (36) with imine 37 in a batch process could be exactly replicated in the flow process (Scheme 10).…”

Synthesis and catalytic applications of C3-symmetric tris(triazolyl)methanol ligands and derivatives

“…48 The same organocatalytic system was previously applied to the asymmetric α-aminoxylation of aldehydes and ketones under bath conditions, 49 for the direct enantioselective aldol reactions in batch 41,47 and for highly enantioselective, syn-diastereoselective Mannich reactions in batch and flow. 50 Another immobilised chiral proline derivative (21b), which contains a longer spacer between the triazole ring and the polymer backbone, was designed for higher catalytic activity and allowed the development of the first practical flow version of highly enantioselective aldol reactions. 51 The PS-supported organocatalyst 21b was efficiently prepared by click reaction between 4-azidoproline derivative 5f and PS-functionalised alkyne 1d catalysed by 6·CuCl under MW irradiation, and subsequent acidic cleavage of protecting groups (Scheme 9).…”

Solvent-controlled diastereoselectivity in tryptophan-catalyzed Mannich reactions

“…Since the pioneering work of List [4,5] and Barbas III [6] on the enantioselective, proline-catalyzed direct Mannich reaction, asymmetric organocatalytic Mannich reactions have become an extraordinarily active area of research. [7][8][9][10] High syn-diastereoselectivity and enantioselectivity can easily be achieved for Mannich adducts derived from substituted aldehyde or ketone donors, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] but a general organocatalyst that can achieve high levels of anti-diastereoselectivity (together with high yields and enantioselectivities) for a wide range of substrates is spotted under UV light (254 nm). Purification by column chromatography was carried out on silica gel Merck 60 (particle size: 0.0040-0.063 nm) using mixtures of DCM/ EtOAc as eluent.…”