Catalysts pyrrolidine-based

Barbas and co-workers [31] have reported a related reaction of a trans-4-aryl-3-buten-2-one, an arylaldehyde, and Meldrum s acid in the presence of catalytic amounts of an amino acid forming spirotriones in good yields and ees (Scheme 9.21). Among a family of 19 pyrrolidine-based catalysts, 5,5-dimethyl thiazolidi-nium-4-carboxylate (DMTC) 113 was found to be the most efficient catalyst for this reaction. 

In 2003, the groups headed by Hayashi [80], Barbas [81], and Cordova [82] simultaneously extended the scope of this asymmetric MCR using aldehyde donors in the presence of chiral pyrrolidine-based catalysts for the so-called enantioselective cross-Mannich reaction (Scheme 16.39). This efficient combination of two different aldehydes has led to a highly stereoselective synthesis of 3-amino aldehydes and y-amino alcohols. Recently, chiral ionic liquids have been efficiently used as catalysts for similar asymmetric Mannich reactions [83]. 

Nitroalkanes are a particularly useful source of stabilised carbanions for the asymmetric addition to electron-poor alkenes. This type of nucleophiles has been added to cyclic and acyclic a,p-unsaturated enones in the presence of a novel class of organocatalysts, such as chiral a-aminophosphonates.This study revealed that the hydrate salt of a pyrrolidine-based catalyst bearing a phosphonate group, depicted in Scheme 1.14, was found to be the best catalytic species, providing, in the presence of tra i-2,5-dimethylpiperazine as an additive, moderate to good results for a range of substrates, as summarised in Scheme 1.14. 

However, the first example of a pyrrolidine-based catalyst working under aqueous conditions reaching a high level of stereoselectivity was the TFA salt of a pyrrolidine derivative bearing long alkyl groups (56, Figure 24.18) [79]. 

Figure 24.24 Proposed role of water in pyrrolidine-based catalysts in the addition of cyclohexanone to nitrostyrenes.

The kinetics and thermodynamics of the formation of E and Zenamines between aldehydes with a-stereocentres and pyrrolidine-based catalysts that lack an acidic proton have been studied as a guide to the probable diastereo- and enantio-selection towards electrophiles when introduced." ... 

Pyrrolidine-based catalysts possessing a tertiary amine functionality were usually employed in the presence of an acid additive. Protonation of the tertiary nitrogen atom can furnish the H-bond donor (Figure 24.24a). Pyrrolidine-based catalyst 56... 

Immobilization of homogeneous catalysts for hydrogenation reactions concerns essentially enan-tioselective hydrogenations, important for the synthesis of fine chemicals (see Chapter 9.2). The pioneering work of Pugin et al.131 concerns the synthesis of a rhodium-based catalyst, with a diphosphine-pyrrolidine-based ligand for the hydrogenation of methylacetamide cinnamate (Equation(8)). 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

Under the reaction conditions used in the one-pot Mannich reaction described above, L-proline (S)-27 was clearly found to be the preferred organocatalyst. As is apparent from Scheme 5.14, the best yield (90%) and enantioselectivity (93% ee) were obtained by use of this organocatalyst [23]. The suitability of all other organo-catalysts used in this one-pot reaction, using 3-methylbutanal as aldehyde, was poor. Remarkably lower yields and poor enantioselectivity were obtained when the thiazolidine catalyst (S)-31 and other pyrrolidine-based organocatalysts were used. 

Two examples of such situations are sketched in Scheme 1.11. Quatemization of tropane occurs mainly from the less hindered pyrrolidine side (equatorial attack at the piperidine ring), even though the main conformer of tropane has an equatorial methyl group. Similarly, l-methyl-2-phenylpyrrolidine yields mainly an anti alkylated product via alkylation of the minor cis conformer when treated with phenacyl bromide [33], In both instances the less stable conformer is more reactive to such an extent that the major product of the reaction results from this minor conformer. A further notable example of a reaction in which the main product results from a minor but more reactive intermediate is the enantioselective hydrogenation of a-acetamidocinnamates with a chiral rhodium-based catalyst [34],... 

The use of different acid functionalities on pyrrolidine-derived catalysts has improved the reaction rate of some aldol reactions. For example, pyrrolidine-based tetrazole derivative 9 (Fig. 2.2) catalyzed many aldol reactions with rates faster than proline, with similar stereocontrol [16, 18b, 24, 55]. The faster reaction rates with tetrazole derivative 9 in DM SO as compared with proline were attributed to the lower pKa of the tetrazole moiety as compared to the carboxylic acid group in DMSO (tetrazole pKa(DMSO) 8.2 acetic acid pKa(DMSO) 12.3) [55, 56]. In addition, tetrazole derivative 9 is more soluble than proline in many organic solvents. A higher actual concentration of the catalyst in the solution phase of a reaction mix-... 

Pyrrolidine-amine-based catalysts such as 18 and 19 can also mediate the addition of ketones to alkylidene malonates (Scheme 2.40) [14]. Aldehydes (e.g., isova-leraldehyde) do not react with vinylidenemalonate 16 under these conditions. 

A catalytic route using a manganese (III) complex has been developed for a-hydroxylation of ketones avoiding the use of water or a protic solvent mixtures of a-hydroxyketones and their silyl derivatives were formed in excellent yield. By using a chiral pyrrolidine-based manganese (III) complex as catalyst, asymmetric oxidation was effected, with enantiomeric excess varying from 14 to 62% [30], Another kind of a-functionalized ketones resulted from silyl enol ethers which after the addition of IOB.BF3 were treated with triethyl phosphite a-ketophosphonates were obtained in this way [31] ... 

Both complexes 12 and 13 are active toward atom-transfer cyclization of N-allyltrichloracetamides [40]. Of particular interest is the synthesis of a pyrrozi-lidine alkaloid skeleton. Much milder conditions are needed when using ruthenium-based catalysts instead of copper derivatives, although a high catalyst loading (30 mol %) is still required. Thus, an N-functionalized vinyl pyrrolidine is smoothly converted at room temperature into a bicyclic lactam, in 90% and 85% yield with complexes 12 and 13, respectively. The product is a precursor of the pyrrozilidine alkaloids trachelantamidine and pseudohehotridane (Eq. 10). 

Group 4 bis(amidate)bis(amido) complexes have also been identified as precatalysts for the more challenging hydroamination of alkenes. The majority of investigations in this field focus on the intramolecular cychzation of aminoalkenes with zirconium-based catalysts. [64e] Neutral group 4 bis(amidate) zirconium amido or imido complexes are efficient precatalysts for the intramolecular cychzation of primary amines to form pyrrolidine and piperidine products (Scheme 12). The monomeric imido complex can be generated by reaction of the bis(amido) complex with 2,6-dimethylaniline and trapped with triphenylphosphine oxide. [64e] The bis(amido) and imido complexes... 

Many communications have concentrated on specific amino phosphonic acids or derivative types. Thus, esters of phosphonoaminoacetic add were obtained by the reactions between trialkyl (ethyl) phosphite and (218) and which are thought to proceed via the phosphorane (219). A sequence has been presented for the preparation of the mono- and di-benzyl esters of N-chz protected (a-aminoben-zyl)phosphonic acid. A synthesis of (aminomethylene)bisphosphonic acid from dibenzylamine, dibenzyl hydrogenphosphonate and triethyl orthoformate has been noted and the asymmetric hydrogenation of (220) in the presence of chiral phosphine catalysts yields samples of (221) with e.e.s of 63-96%. The pyrrolidine-based compound (222) has been prepared from methyl S)-N-methoxycarbonyl-4-oxo-2-pyrrolidinecarboxylate and iV-coupled 4-amino-butanal diethyl acetals were the starting materials in syntheses of the pyrrolidine-2-phosphonic add derivatives (223) in which Z represents the iV-protected amino add or peptide moiety. ... 

The use of o-ribonolactone derived pyrrolidines as chiral catalysts for the addition of diethylzinc to aldehydes is mentioned in Chapter 24 and the synthesis of the pyrrolidine based antibiotic (+)-preussin is covered in Chapter 19. 

Nal chiral amines such as DBU, ° (S)-2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine, C2-symmetric (2S,55)-2,5-diphenylpyrrolidine, (-)-quinine, and proline polymer catalysts such as antibody 38C2" and polymer-anchored chiral catalysts and solid base catalysts such as MgO and Mg-Al-O-r-Bu hydrotalcite. Furthermore, the solvent-free Michael addition has been established by application of CeCb 7H20-NaI as catalyst or microwave irradiation of reactants on BiCb or Cdh, EuCb, CeCb 5H20, and alumina surfaces. It is interesting that the thermal treatment or microwave irradiation of 1,5-ketodiesters or 1,5-diketones in DMSO in the presence of NaX (X = Cl, Br, I) results in the retro-Michael addition. ... 

Figure 2.6 Some chiral pyrrolidine-based amines employed as catalysts in the enantioselective Michael addition of aldehydes to nitroalkenes.

The synthesis of heterocycles by means of Lewis bases has been carried out using the reactions described above. For instance, the dipole resulting from the reaction of pyridine with DMAD was intercepted with phenylisocyanate giving a 1,4 dipole that ultimately led to pyrimidindione derivatives. Wang and coworkers have described the synthesis of benzoxazoles by reaction of ynals with N-protected-2-aminophenols using pyrrolidine as catalyst. Salicylaldehyde has been the starting material for the synthesis of many benzoheterocycles. When using DBU as catalyst, it was transformed into benzopyran derivatives by reaction with 2,2-disubstituted allene esters. When DABCO is used as catalyst, the reaction of AT-tosylimines with ethyl... 

In 2001, Yamamoto prepared various chiral diamines (pyrrolidine based secondary and tertiary amines) " and screened a range of protic acids to catalyse the aldol reaction. Catalyst la TfOH, had no catalytic activity alone. However, the combination of diamine la and la TfOH catalysed the aldol reaction of ketones with p-nitrobenzaldehyde. The aldol products were obtained with high chemical yields and reasonable to high enantio- and diastereoselectivities (Scheme 9.1). ... 

Alexakis et al. proposed in 2010 the use of aminals deriving from 4-hydroxyproline for the asymmetric addition of aliphatic aldehydes to vinyl sulfones." " The idea that a fluorine atom at the C4 position of these pyrrolidine-based organocatalysts could be used to favour one single reactive enamine conformation was further exploited by the same authors in 2011, designing a catalyst (28) able to afford excellent yields and enantioselec-tivities (Scheme 11.24). ... 

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