Ammonium aldol reactions

The first promising asymmetric aldol reactions through phase transfer mode will be the coupling of silyl enol ethers with aldehydes utilizing chiral non-racemic quaternary ammonium fluorides,1371 a chiral version of tetra-n-butylammonium fluoride (TBAF). Various ammonium and phosphonium catalysts were tried138391 in the reaction of the silyl enol ether 41 of 2-methyl-l-tetralone with benzaldehyde, and the best result was obtained by use of the ammonium fluoride 7 (R=H, X=F) derived from cinchonine,1371 as shown in Scheme 14. 

For enantioselective aldol reactions using chiral quaternary ammonium ions see Horikawa M, Busch-Petersen J, Corey EJ (1999) Tetrahedron Lett 40 3843... 

Subsequent ion exchange of the metal cation with the quaternary ammonium ion catalyst provides a lipophilic ion pair (step 2), which either reacts with the requisite alkyl electrophile at the interface (step 3) or is partitioned into the electrophile-containing organic phase, whereupon alkylation occurs and the catalyst is reconstituted. Enantioselective PTC has found apphcation in a vast number of chemical transformations, including alkylations, conjugate additions, aldol reactions, oxidations, reductions, and C-X bond formations." ... 

In contrast to these vapour-phase reactions, it has been reported that ketones and aqueous ammonia (or ammonium acetate) in an autoclave give less complex mixtures of pyridines. Crotonaldehyde gives 5-ethyl-2-methylpyridine (570) in up to 59% yield, methyl vinyl ketone gives 2,3,4-trimethylpyridine (571) rather than 2,3,6-trimethylpyridine 1,3,3-trimethoxybutane has been used in place of methyl vinyl ketone (49JA2629). In some cases reverse aldol reactions occur (for example with benzalacetophenone) giving unwanted products. A similar reverse aldol is responsible for the production of triarylpyridines (572) when benzalacetophenones are treated with formamide and ammonium formate (73JA4891). 

Carbonyl Addition Diethylzinc has been added to benzaldehyde at room temperature in the presence of an ephedra-derived chiral quat (8) to give optically active secondary alcohols, a case in which the chiral catalyst affords a much higher enantioselectivity in the solid state than in solution (47 to 48, Scheme 10.6) [30]. Asymmetric trifluoromethylation of aldehydes and ketones (49 to 50, Scheme 10.6 [31]) is accomplished with trifluoromethyl-trimethylsilane, catalyzed by a quaternary ammonium fluoride (3d). Catalyst 3d was first used by the Shioiri group for catalytic asymmetric aldol reactions from silyl enol ethers 51 or 54 (Scheme 10.6) [32]. Various other 1,2-carbonyl additions [33] and aldol reactions [34] have been reported. 

Recently, Castle and coworkers introduced C3-alkyny]-substituted chiral quaternary ammonium salt of type 41, and evaluated its ability as a chiral phase-transfer catalyst in the aldol reaction between 1 and hydrocinnamaldehyde using BTTP as a base, in which a high level of enantioselectivity (91% ee) was observed for syn-22 (Scheme 2.19) [41],... 

The group of Arai and Nishida investigated the catalytic asymmetric aldol reaction between tert-butyl diazoacetate and various aldehydes under phase-transfer conditions with chiral quaternary ammonium chloride 4c as a catalyst. The reactions were found to proceed smoothly in toluene, even at —40°C, when using 50% RbOH aqueous solution as a base, giving rise to the desired aldol adducts 23 with good enantioselectivities. The resulting 23 can be stereoselectively transformed into the corresponding syn- or anti-P-hydroxy-a-amino acid derivatives (Scheme 2.20) [42],... 

Maruoka and coworkers recently developed an efficient, highly diastereo- and enantioselective direct aldol reaction of glycine Schiff base 2 with a wide range of aliphatic aldehydes under mild phase-transfer conditions employing N-spiro chiral quaternary ammonium salt li as a key catalyst, as shown in Table 5.12 [41a]. 

Mechanistic investigations revealed the intervention of a highly stereoselective retro aldol reaction, which could be minimized by using a catalytic amount of 1% NaOH aqueous solution and ammonium chloride, leading in turn to the establishment of a general and practical chemical process for the synthesis of optically active anti-P-hydroxy-a-amino esters 78 (Table 5.13) [41b],... 

The usefulness of the present system was then demonstrated by its application to the in-situ generation of structurally rigid, C2-symmetric chiral quaternary ammonium fluorides of type 6 (X = F) from the corresponding hydrogen sulfate 6 (X = H S04), and their direct use for the asymmetric aldol reactions (Scheme 9.3). For instance,... 

Table 9.1 Asymmetric Mukaiyama-type aldol reactions of a glycine derivative catalyzed by in situ-generated chiral quaternary ammonium fluoride.

Table 9.2 Asymmetric Mukaiyama aldol reactions catalyzed by chiral quaternary ammonium fluorides4b with various methods of preparation.

Table 9.3 Asymmetric aldol reactions of enol silyl ethers with benzaldehyde catalyzed by chiral quaterna7 ammonium fluorides 4b or 4c.

Several approaches have been developed for the synthesis of 3-deoxy-D-mararao-oct-2-ulosonic acid (Kdo, 123) the most common one involves the coupling of oxaloacetic acid with D-arabinose followed by decarboxylation. This aldol reaction takes place under basic conditions, but above pH 11 side reactions occur. The procedure is simple and Kdo is isolated as the crystalline ammonium salt.316... 

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

Table 4.1 The chiral ammonium bifluoride 12-catalyzed asymmetric Mukaiyama-type aldol reaction of ketene silyl acetal 13 with aldehydes. (For experimental details see Chapter 14.1.5)...

Quaternary Ammonium Fluoride-Mediated Mukaiyama-Type Asymmetric Aldol Reaction [4] (p. 122)... 

Quaternary Ammonium Salt-Mediated Asymmetric Direct Aldol Reaction of Glycinate Benzophenone Schiff Base with 3-Phenylpropanal Under Phase-Transfer Conditions [6] (p. 145)... 

Worth mentioning are chiral gold complexes [20d, e] as well as chiral quaternary ammonium fluorides [21], which are used successfully as catalysts in the asymmetric aldol reaction. 

Reymond, J.L. and Chen, Y.W. (1995) Catalytic, enantioselective aldol reaction using antibodies against a quaternary ammonium ion with a primary amine cofactor. Tetrahedron Letters, 36, 2575-2578. 

Many of the classical methods grew out of the earliest synthesis of imidazole, which was achieved in 1858 by Debus [1] when he allowed glyoxal, formaldehyde and ammonia to react together. Although the earliest modifications of this method used a-diketones or a-ketoaldehydes as substrates [2, by the 1930s it was well established that a-hydroxycarbonyl compounds could serve equally well, provided that a mild oxidizer (e.g. ammoniacal copper(ll) acetate, citrate or sulfate) was incorporated [3. A further improvement was to use ammonium acetate in acetic acid as the nitrogen source. All of these early methods have deficiencies. There are problems associated with the synthesis of a wide range of a-hydroxyketones or a-dicarbonyls, yields are invariably rather poor, and more often than not mixtures of products are formed. There are, nevertheless, still applications to the preparation of simple 4-alkyl-, 4,5-dialkyl(diaryl)- and 2,4,5-trialkyl(triaryl)imidazoles. For example, pymvaldehyde can be converted quite conveniently into 4-methylimidazole or 2,4-dimethylimidazole. However, reversed aldol reactions of pyruvaldehyde in ammoniacal solution lead to other imidazoles (e.g. 2-acetyl-4-methylimidazole) as minor products [4]. Such... 

---