Prolines water aldol reaction

Reaction progress kinetic analysis offers a reliable alternative method to assess the stability of the active catalyst concentration, again based on our concept of excess [e]. In contrast to our different excess experiments described above, now we carry out a set of experiments at the same value of excess [ej. We consider again the proline-mediated aldol reaction shown in Scheme 50.1. Under reaction conditions, the proline catalyst can undergo side reactions with aldehydes to form inactive cyclic species called oxazolidinones, effectively decreasing the active catalyst concentration. It has recently been shown that addition of small amounts of water to the reaction mixture can eliminate this catalyst deactivation. Reaction progress kinetic analysis of experiments carried out at the same excess [e] can be used to confirm the deactivation of proline in the absence of added water as well to demonstrate that the proline concentration remains constant when water is present. 

In the (S)-proline-catalyzed aldol reactions, the addition of a small amount of water did not affect the stereoselectivities [6]. However, a large amount of water often resulted in products with low enantiomeric excess water molecules interrupt the hydrogen bonds and ionic interactions critical for the transition states that lead to the high stereocontrol. For example, in the (S)-proline-catalyzed aldol reaction of acetone and 4-nitrobenzaldehyde in DMSO, the addition of 10% (v/v) water to the reaction mixture reduced the ee-value from 76% (no water) to 30% [6]. Note that the addition of a small amount of water into (S)-proline-catalyzed reactions often accelerates the reaction rate, and the addition of water should be investigated when optimizing these reactions [61]. 

Dual mechanism of zinc-proline catalyzed aldol reactions in water. Chemical Communications (Camhridge, England), 1482-1484. 

The proline-catalysed aldol reaction of tetrahydro-4/f-thiopyran-4-one with aldehydes, which is accelerated by water <04SL1891>, gives the anti adducts with high diastereo- and enantioselectivity DMSO is the solvent of choice for aliphatic aldehydes and moist DMF for aromatic examples (Scheme 23). Desulfurisation of these thiopyrans with Raney-Ni gives products equivalent to aldol products derived from pentan-3-one <04TL8347>. 

Despite the high catalyst loading, the rate of the proline-catalyzed aldol reaction is very low. However, regardless of an aromatic aldehyde, the reaction time can be significantly shortened via microwave irradiation [16]. The addition of either acidic or basic co-catalysts slows down the reaction. Water has a beneficial effect on the reactivity [17]. On the other hand, extensive studies by Armstrong and Blackmond have revealed that water slows down the rate of the reaction but at the same time decreases the amount of side reactions [18]. In some cases, when the reaction was run using a chiral additive co-catalyst and a large excess of water, increased... 

The proline-catalyzed aldol reaction of cyclohexanone (57) with 4-nitrobenzal-dehyde (2a) in DMSO affords the desired aldol anti-SSa with good yield but rather low stereoselectivity (Scheme 3.15) [14]. However, the addition of water led to an increase both in the yield and enantioselectivity, though the reaction rate remained [17]. 

The use of ball mills to assist solvent-free asymmetric organocatalytic processes is still very rare. In 2006 Bohn and coworkers [59] reported the first examples of such applications. This technique was used in a proline catalyzed aldol reaction between ketones and aromatic aldehydes. The asymmetric organocatalytic aldol reaction was very intensively studied since the pioneering work by list and Barbas in 2000/2001 [21]. In the vast majority of cases it was performed in different organic solvents (e.g., DMSO, DMF), but in recent years several eco-friendly solvent-free, or using water, protocols have been reported. Such reactions, avoiding the use of organic solvents, are especially preferred in industrial-scale processes and the synthesis of pharmaceuticals. 

What is the role of water under these conditions It has been suggested that water suppresses the formation of proHne-oxazoUdinone, which has been considered to be a parasitic species [11]. Then, the role of water is to prevent deactivation rather than to promote activity. Studies, carried out on the proUne-catalyzed reaction between acetone and 2-chlorobenzaldehyde allow one to hypothesize a conflicting role of water. Water increases the total catalyst concentration due to suppression of unproductive species and decreases the relative concentration of productive intermediates by shifting the iminium ion back to proline [12]. Addition of water suppresses formation of both on- and ofF-cyde iminium ions 1 and 2 by Le Chatelier s principle (Scheme 24.2a). The net effect of added water on the globally observed rate will depend on the relative concentrations of iminium ions 1 and 2, which may be different for different aldehydes and can be a function of substrate concentrations and rate and equilibrium constants. Seebach and Eschen-moser have raised doubts about the fact that oxazoUdinones are unproductive and parasitic species in proline-catalyzed aldol reactions [13]. The small excess of water will potentially facilitate proton-transfer in the transition state (Scheme 24.2b), which both lowers the LUMO of the incoming electrophile as well as directs the enantioselectivity of the newly formed stereocenters. 

Experimentally, the low solubility of proline in common organic solvents is a problem for the proline-catalyzed aldol reaction [40]. The problem can be circumvented by using polar aprotic solvents like DMSO [4]. Water can also be used as co-solvent it speeds up the reaction and allows using only stoichiometric quantities of ketones [40]. The reaction still works when performed in water with no other co-solvent, but to the price of a loss of selectivity [40]. 

Rate acceleration in the proline-catalyzed aldol reaction without negative effect, or even with a positive effect, on stereoselectivity was observed when water was used at up to 500mol% in DMF solution [10]. 

Lewis-Acid Catalyzed. Recently, various Lewis acids have been examined as catalyst for the aldol reaction. In the presence of complexes of zinc with aminoesters or aminoalcohols, the dehydration can be avoided and the aldol addition becomes essentially quantitative (Eq. 8.97).245 A microporous coordination polymer obtained by treating anthracene- is (resorcinol) with La(0/Pr)3 possesses catalytic activity for ketone enolization and aldol reactions in pure water at neutral pH.246 The La network is stable against hydrolysis and maintains microporosity and reversible substrate binding that mimicked an enzyme. Zn complexes of proline, lysine, and arginine were found to be efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in an aqueous medium to give quantitative yields and the enantiomeric excesses were up to 56% with 5 mol% of the catalysts at room temperature.247... 

The aldol reaction in water is also efficiently catalyzed by polymers 127 and 128, in which the proline moieties are anchored using a different strategy [331]. In this case the N-BOC protected hydroxyproline is reacted with chloromethylstyrene and... 

The anri-selective aldol reaction between cyclohexanone and ArCHO reaches >99% ee if it is conducted in the presence of trawi -4-(4-t-butylphenoxy)-L-piDline and sulfated P-cyclodextrin in water at room temperature. Another catalyst is cw-A-fl-adamantane-carboxamido)-(5)-proline (1) in conjunction with P-cyclodextrin. ... 

Now we are prepared to illustrate these experimental protocols of reaction progress kinetic analysis using data from reaction calorimetric monitoring of the aldol reaction shown in Scheme 27.1. We turn hrst to the issue of catalyst stability using our same excess protocol. In these aldol reactions, it was noted that the active catalyst concentration can be effectively decreased by the formation of oxazolidinones between proline and aldehydes or ketones, and that addition of water can suppress this catalyst deactivation. Same excess reactions carried out in the absence of water and in the presence of water are shown in Figure 27.3a and Figure 27.3b, respectively. The plots do not overlay in the absence of water, but they do when water is present. The overlay in these same [e] experiments in Figure 27.3b means that the total concentration of active catalyst within the cycle is constant and is the same in the two experiments where water is present. 

A representative set of such structures (7.80-7.86) is shown, all of which result in the formation of aldol adducts with high ee. Replacement of the carboxylic acid moiety with a bioisosteric tetrazole results in a catalyst (7.80) that is both more reactive than L-proline (7.66) and more readily soluble in organic solvents such as THF.38a.b jji a similar vein, acyl sulfonamides such as (7.81) give good enantios-electivities in the aldol reaction with aromatic aldehydes in organic solvents such as dichloromethane and acetone. 3 The addition of stoichiometric amounts of water increases the activity of tetrazole (7.80) further and this allows the use of aldehydes such as chloral monohydrate (7.87) and formaldehyde, which have an affinity for water and are generally poor substrates for the catalytic asymmetric aldol reaction. 38 = Catalysts (7.82)38 (7.33) 3Sd ijpophilic substiments,... 

K. Liu, D. Haussinger, W.-D. Woggon, Aldol reactions in water using a j3-cyclodextrin-binding proline derivative, Synlett., 2007, 3, 2298-2300. 

In the aldol reaction itself, proline s carboxyl group has a key role to play because it can participate in a hydrogen bond that organizes the slx-membered transition state in such a way that only one of the possible enantiomeric products can form. The diagram below shows how. Water generated in the initial condensation hydrolyses the iminium product of the aldol and regenerates the proline catalyst. 

Reproduced from HemMez JG, Juaristi E Efficient ball-mill procedure in the green asymmetric aldol reaction organocatalyzed by (S)-proline-containing dIpeptides in the presence of water. Tetrahedron 2011 67 6953-9. Copyright (2011), with permission from Elsevier. 

In continuation of synthetic study, Juaristi and coworkers investigated the efficacy of the series of (5 )-proline-thioamide catalysts C4-C6 (Chart 2.1) [35]. When aldol reaction of 3-nitrobenzaldehyde with cyclohexanone was carried out, the best results were obtained when using 7 mol % of catalyst C4. On the other hand, in ball-milling conditions at -20°C the use of water and acidic additives was beneficial for the increase of diastereoselectivity in favor of the anfi-diastereomer however, the enantiomeric excess of the process was not improved. Thus, reactions between cyelic ketones and aromatic were carried out in conditions identical to these in Table 2.35 to afford aldol products in good isolated yields (70-89%) with high diastereo- (92 8 to >98 2 anti/syn) and enantioselectivities (82-96% ee) (Table 2.37). 

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