Ketones, 3-amino Mannich reaction

In a second attempt to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, we have used the Mannich reaction to convert a ketone-activated monodentate dienophile into a potentially chelating p-amino ketone. The Mannich reaction seemed ideally suited for the purpose of introducing a second coordination site on a temporary basis. This reaction adds a strongly Lewis-basic amino functionality on a position p to the ketone. Moreover, the Mannich reaction is usually a reversible process, which should allow removal of the auxiliary after the reaction. Furthermore, the reaction is compatible with the use of an aqueous medium. Some Mannich reactions have even been reported to benefit from the use of water ". Finally, Lewis-acid catalysis of Mannich-type reactions in mixtures of organic solvents and water has been reported ". Hence, if both addition of the auxiliary and the subsequent Diels-Alder reaction benefit from Lewis-acid catalysis, the possibility arises of merging these steps into a one-pot procedure. 

Apparently, 4.54 is extremely reluctant to undergo a retro Mannicli reaction. Riviere demonstrated that this behaviour is not unusual for (3-amino ketones. From the study of a large number of Mannich adducts. Riviere concludes that the retro Mannich reaction requires an aromatic group next to the carbonyl functionality. Qearly, 4.54 lacks this arrangement. 

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

An a-amino acid 3 can be prepared by treating aldehyde 1 with ammonia and hydrogen cyanide and a subsequent hydrolysis of the intermediate a-amino nitrile 2. This so-called Strecker synthesis - is a special case of the Mannich reaction-, it has found application for the synthesis of a-amino acids on an industrial scale. The reaction also works with ketones to yield a, a -disubstituted a-amino acids. 

Substitution of an alicyclic ring for one of the aromatic rings in the amino alcohols such as 32 or 39 produces a series of useful antispasmodic agents that have found some use in the treatment of the symptoms of Parkinson s disease. Mannich reaction of acetophenone with formaldehyde and piperidine affords the amino-ketone, 44a. Reaction of the ketone with cyclohexylmagnesium... 

A particularly useful variation of this reaction uses cyanide rather than HCN. a-Amino nitriles can be prepared in one step by the treatment of an aldehyde or ketone with NaCN and NH4CI. This is called the Strecker synthesisand it is a special case of the Mannich reaction (16-15). Since the CN is easily hydrolyzed to the acid, this is a convenient method for the preparation of a-amino acids. The reaction has also been carried out with NH3-I-HCN and with NH4CN. Salts of primary and secondary amines can be used instead of NH to obtain N-substituted and N,N-disubstituted a-amino nitriles. Unlike 16-51, the Strecker synthesis is useful for aromatic as well as aliphatic ketones. As in 16-51, the Me3SiCN method has been used 64 is converted to the product with ammonia or an amine. ... 

A propoxyphene-like analgesic which obeys the empirical morphine rule is pyrroliphene (101). A Mannich reaction involving pyrrolidine, formaldehyde and propiophenone gave amino ketone 99, which was converted to tertiary carbinol 100 by reaction with benzyl magnesium chloride reaction with acetyl... 

Three years after the discovery of the asymmetric BINOL phosphate-catalyzed Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended these transformations to the use of simple ketones as nucleophiles (Scheme 25) [44], Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence of chiral phosphoric acids (R)-3c, (/ )-14b, or (/ )-14c (0.5-5 mol%, R = Ph, 4-Cl-CgH ) to give P-amino carbonyl compounds 69 or 70 in good yields (42 to >99%), flnfi-diastereoselectivities (3 1-49 1), and enantioselectivities (72-98% ee). 

This protocol complements Akiyama s method which provides P-amino carbonyl compounds as i yn-diastereomers [14], It tolerated aromatic, heteroaromatic, and aliphatic aldehydes. Cyclic ketones, acetone, as well as acetophenone derivatives could be employed. The use of aromatic ketones as Mannich donors was up to that time unprecedented in asymmetric organocatalysis. Rueping et al. independently expanded the scope of the asymmetric Brpnsted acid-catalyzed Mannich reaction of acetophenone [45]. 

The condensation between an aldehyde, an amine and an active methylene compound, named after Carl Mannich, was first published in 1912 [4]. The products of the reaction, a-amino ketones or Mannich bases are important compounds with numerous applications in the synthesis of pharmaceuticals and of natural products [7]. 

Systematic investigations of the catalyst structure-enantioselectivity profile in the Mannich reaction [72] led to significantly simplified thiourea catalyst 76 lacking both the Schiff base unit and the chiral diaminocyclohexane backbone (figure 6.14 Scheme 6.88). Yet, catalyst 76 displayed comparable catalytic activity (99% conv.) and enantioselectivity (94% ee) to the Schiff base catalyst 48 in the asymmetric Mannich reaction of N-Boc-protected aldimines (Schemes 6.49 and 6.88) [245]. This confirmed the enantioinductive function of the amino acid-thiourea side chain unit, which also appeared responsible for high enantioselectivities obtained with catalysts 72, 73, and 74, respectively, in the cyanosilylation of ketones (Schemes 6.84 and 6.85) [240, 242]. 

Support-bound C-nucleophiles have also been successfully added to imines. Poly-styrene-bound thiol esters can be converted into ketene acetals by O-silylation, and then alkylated with imines in the presence of Lewis acids. Further examples include Mannich reactions of support-bound alkynes and indoles (Table 10.10). Some Man-nich-type products (e.g. 3-(aminomethyl)indoles, 2-(aminomethyl)phenols, (3-amino ketones) are unstable and can decompose upon treatment with acids. 3-(Amino-... 

Exercise 17-21 a. A useful modification of aldol addition to methanal, known as the Mannich reaction, uses a secondary amine (usually as its hydrochloride salt) to selectively introduce one carbon atom at the alpha position of an aldehyde or ketone. The actual product is the salt of an amino ketone. For example,... 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

Aube and co-workers have found that enolizable ketones react with benzyl azide in triflic acid to yield /V-(phenylamino)-methylated products [Eq. (5.354)]. The transformation is an aza-Mannich reaction interpreted with the involvement of the Mannich reagent A -phenyl iminium ion 295 formed in situ in a Schmidt rearrangement. Cyclic tertiary alcohols react with alkyl azides in triflic acid to yield N-alkylamines (296, 297)983 [Eq. (5.355)]. The Schmidt rearrangement was used to transform Merrifield resin into amino-polystyrene resin by reacting the azido derivative in excess triflic acid (CH2CI2, 0°C).984... 

The intermolecular Mannich reaction combines an aldehyde, an amine and an enolizable carbonyl compound for the one-pot synthesis of yfi-amino ketones or... 

The Mannich reaction [18, 19] is a widely applied means of producing /i-amino carbonyl compounds starting from cheap and readily available substrates. In this reaction an aldehyde 20, an amine 21, and a ketone 22 react in a three-component-one-pot synthesis (Scheme 5.12, pathway 1). As a synthetic alternative, the reaction can also be performed as a nucleophilic addition of a C-nucleophile 22 to a preformed imine 24 which is prepared starting from the aldehyde and an amine source (Scheme 5.12, pathway 2). 

The Mannich reaction using PMP-protected a-imino glyoxylate, 33, can also be conducted enantio- and diastereoselectively when using substituted acetone derivatives, as has been successfully shown by the Barbas group [26-28]. Several types of ketone are accepted as donors in the presence of 20 mol% of L-proline as catalyst [26]. This type of Mannich reaction provides keto-functionalized syn a-amino acid... 

In conclusion, this new organocatalytic direct asymmetric Mannich reaction is an efficient means of obtaining optically active //-amino carbonyl compounds. It is worthy of note that besides the enantioselective process, enantio- and diastereose-lective Mannich reactions can also be performed, which makes synthesis of products bearing one or two stereogenic centers possible. Depending on the type of acceptor or donor, a broad range of products with a completely different substitution pattern can be obtained. The range of these Mannich products comprises classic / -amino ketones and esters as well as carbonyl-functionalized a-amino acids, and -after reduction-y-amino alcohols. 

M. C. Sharma, A. K. Garcia, J. M. Gonzalez, A. Landa, C. Linden, A. a-Oxymethyl ketone enolates for the asymmetric Mannich reaction. From acetylene and N-alkoxycarbonylimines to /J-amino acids. Angew. Chem. Int. Ed. 2000, 39, 1063-1065. 

We need a formaldehyde equivalent that is less electrophilic than formaldehyde itself and will therefore add only once to enol(ate)s. The solution is the Mannich reaction.7 Formaldehyde is combined with a secondary amine to give an iminium salt that adds 47 to the enol of the aldehyde or ketone in slightly acidic conditions to give the amino ketone (or Mannich base ) 48. If the product of the aldol reaction 50 is wanted, alkylation on nitrogen provides a good leaving group and ElcB elimination does the trick. 

A further application of L-proline as a catalyst in asymmetric synthesis, which was found by List, is the three-component-Mannich reaction for the preparation of /1-amino ketones [12]. In the presence of L-proline as a catalyst the Mannich product 6 has been obtained in 50% yield and with 94% ee (Scheme 5, reaction 1). 

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