Carbonyl compounds P-amino

Mannich and related readions provide one of the most fundamental and useful methods for the synthesis of p-amino carbonyl compounds, which constitute various pharmaceuticals, natural products, and versatile synthetic intermediates.1271 Conventional protocols for three-component Mannich-type readions of aldehydes, amines, and ketones in organic solvents indude some severe side reactions and have some substrate limitations, espedally for enolizable aliphatic aldehydes. The dired synthesis of P-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view. Our working hypothesis was that aldehydes could read with amines in a hydro-phobic reaction fidd created in water in the presence of a catalytic amount of a metal triflate and a surfactant to produce imines, which could then read with hydrophobic silyl enolates. 

P-amino carbonyl compound, and the reaction is now called the Mannich reaction [206, 207],... 

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]. 

In 2004, Kobayashi et al. introduced enecarbamates as nucleophiles to asymmetric catalysis [48], The addition of enecarbamates to imines in the presence of a chiral copper complex provides access to P-amino imines which can be hydrolyzed to the corresponding p-amino carbonyl compounds [49],... 

P-Amino carbonyl compounds containing an a-atkyUdene group are densely functionalized materials, which are widely applied in the synthesis of medicinal reagents and natural products [265]. These products are usually prepared through the classic aza-Morita-Baylis-Hillman reaction [176, 177] of activated imines and electron-deficient alkenes catalyzed by tertiary amines or phosphines. Chen and co-workers, in 2008, identified bis-thiourea 106 as a suitable catalyst for the... 

Keywords Mannich reaction, p-Amino carbonyl compounds, Imine, Enolate... 

The aza-Michael reaction yields, complementary to the Mannich reaction, P-amino carbonyl compounds. If acrylates are applied as Michael acceptors, P-alanine derivatives such as 64 and 65 are obtained. The aza-Michael reaction can be catalyzed by Bronsted acids or different metal ions. Good results are also obtained with FeCl3, as shown in Scheme 8.29. The addition of HNEt2 to ethyl acrylate (41f), for example, requires 10mol% of the catalyst and a reaction time of almost 2 days [94], The addition of piperidine to a-amino acrylate 41g is much faster and yields a,P-diaminocarboxylic acid derivative 65 [95]. 

Amines are good nucleophiles for conjugate addition reactions, and give products that we can term p-amino carbonyl compounds (the new amino group is P to the carbonyl group). Dimethylamine is a gas at room temperature, and this reaction has to be carried out in a sealed system to give the ketone product. 

Strategy C. The Broensted acid 16 smoothly catalyses the Mannich reaction shown in Figure 15, affording the corresponding P-amino carbonyl compounds in excellent yield and short reaction times. ... 

The most attractive part of this work is that [bmim] [OH] is easily recycled and can be reused without obvious loss of the catalytic activity. This approach could make a valuable contribution to the synthesis of P-amino carbonyl compounds. 

Gong K, Dong F, Wang HL, Liu ZL (2007) Basic functionalized ionic liquid catalyzed one-pot Mannich-type reaction three component synthesis of P-amino carbonyl compounds. Monatsh fur Chemie 138 1195-1198... 

A variety of polycyclic A-heterocycles have been synthesised from 5-(3-halo-4-methoxyphenyl)thianthrenium perchlorates 40 by treatment with LDA in the presence of P-amino carbonyl compounds. The reaction involves the generation of 3-halo-4-methoxybenzyne, with thianthrene as the leaving group <05JOC5741>. 

A-Acyliminium ion 193 generated by anodic oxidation of 192 reacted with alkenes and alkynes to give y-aminoalcohols and P-amino carbonyl compounds, respectively, after treatment with H20/NEt3. With vinyltrimethylsilane the reaction was highly diastereoselective affording enantiomerically pure a-silyl-y-amino alcohol 194 <040L2709>. 

P-Amino carbonyl compounds. Condensation of aldehydes, amines, and ketene silyl acetals is promoted by HBF4 in an aqueous media (aq t-PrOH or in the presence of... 

Asymmetric Mannich (imine-aldol) reactions give optically active p-amino carbonyl compounds of biological activity. There are two types of Pd-catalyzed asymmetric Mannich-type reactions Lewis acid catalyzed and Pd-enolate reactions. These reactions proceed similarly, but the reaction mechanisms are quite different. 

The Mannich reaction serves for the preparation of a wide range of p-amino carbonyl compounds. Furthermore, the Mannich adducts can be easily reduced or oxidised and then deprotected to give the corresponding p-amino acids and p-amino alcohols. Jorgensen showed that catalyst C2a was able to catalyse the Mannich reaction. Similarly, Cordova and coworkers used catalyst Cla in the same reaction. Velilla and coworkers used catalyst C8 in the reaction of butyraldehyde with iV-tosylimines, but selectivity was only moderate. However, catalyst C9, based on 4-hydro-xyproline was considerably more enantioselective (99% enantiomeric excess) (Scheme 8.33). 

Kim and coworkers have reported a synthetic route to diverse heterocyclic compounds through the nucleophihc addition of P-amino carbonyl compounds 79 to 3-halo-4-methoxybenzynes 78 (Scheme 12.25) [51]. The benzyne intermediate 78 was generated from 5-(3-halo-4-methoxyphenyl)thianthrenium perchlorates 77 upon treatment with lithium diisopropylamide (LDA) in THF at reflux. P-Amino carbonyl compounds, such as P-amino ketones, esters, amides and aldehydes, all react smoothly with benzyne 78 under the reported reaction conditions. Moreover, bis(2-aminophenyl) disulfide, 2-aminophenyl benzenesulfonate... 

The asymmetric Mannich reaction represents one of the most useful transformations for the synthesis of p-amino carbonyl compounds and their... 

The Mannich reaction represents a useful extension of aldol-type approaches for the stereoselective formation of C-C bonds with concomitant introduction of O- and N-functionality. In this reaction two carbraiyl compounds and an amine react to form p-amino-carbonyl compounds. Besides indirect variants using preformed enolates the use of unmodified nucleophiles (direct variant) has attracted considerable interest (92). Therefore, it is not surprising that the first example of a direct organocatalytic Mannich reaction was published only shortly (93) after the first proline-catalyzed aldol reaction (28). p-Anisidine (102) is commonly used for... 

The Mannich reaction, historically, has involved the condensation of formaldehyde, a primary or secondary amine, and an enolizable carbonyl compound. The resultant P-amino-carbonyl compound, or Mannich base, requires protic solvents and high reaction temperatures for its formation. 

Alternatively, Garter s group has worked on the synthesis of (5)-Af-(p-dodecylphenylsulfonyl)-2-pyrrolidinecarbox-amide ((6)-20) and its use as organocatalyst for the direct Mannich reaction (Scheme 2.5) [22], obtaining the p-amino carbonyl compounds 21 and 22 as well as the y-amino alcohol 23, after a reduction with NaBH. ... 

A highly diastereoselective synthesis of azetinyl thiazolidine-2-thiones has been achieved by addition of the chlorotitanium enolates of N-acyl thiazolidine-2-thiones to O-methyl aldoximes [103], where the antV azetines product can be subsequently converted to the corresponding P-amino carbonyl compounds with retention of stereochemistry (Scheme 14.35). 

Enantioselective Mannich-type addition of enolate equivalents to imines continues to be an attractive strategy for the preparation of chiral p-amino carbonyl compounds. In the area of copper-catalyzed enantioselective Mannich reactions, a number of outstanding examples have appeared in this decade. In particular, work from Kobayashi s laboratories has led this field in recent years. Kobayashi and coworkers have developed a Cu(OTf) 2/diamine catalyst (121) for highly enantioselective addition of enolate equivalents to N-acylimino esters [36]. This methodology... 

Metal salt catalyzed conjugate addition of nitrogen nucleophiles has attracted considerable interest as means to access valuable intermediates for the preparation of P-amino acid, P-lactams, isoxazolidinones, aziridines, and so on. However, enantios-elective Cu(II)-catalyzed reactions of this type are limited. Cardillo and coworkers reported the Cu(OTf)2/Bn-BOX (32)-catalyzed additions of O-benzylhydroxylamine (230) and N,0-bis(trimethylsilyl)hydroxylamine (232) to alkylidene malonates (219) (Scheme 17.49) [68]. Yields and enantioselectivities ofthedesired P-amino carbonyl compounds (231) and (233) are moderate to good under optimized conditions. In the latter case the conjugate addition products are readily converted to enantiomerically enriched aziridines (234) in good yields. 

Asymmetric Mannich-type reaction is a versatile method to prepare nonracemic P-amino carbonyl compounds, which can be transformed into P-lactams or related compounds. Lectka and coworkers have shown that a BINAP-silver(I) complex acts as asymmetric catalyst in the reaction of a-imino esters for the first time in 1998 [58]. The chiral silver (I) catalyst has been further applied to asymmetric ene reactions of a-imino esters [59, 60]. In contrast, Hoveyda and co workers have developed a new chiral silver(I) catalyst using iso-Leu-derived phosphine (44) as a chiral ligand, which promotes asymmetric Mannich reaction of silyl... 

Disconnection of TM 2.17a requires new knowledge. This stmcture corresponds to the Mannich base since the terf-amino group is present in the fl-posilion to the strong electron-withdrawing nitro group. The retra-Mannich type disconnection of two bonds leads to simple starting materials, piperidine, formaldehyde and 2-nitropropane. In the same scheme are proposed reaction conditions for the synthesis of TM 2.17. More details on the Mannich reaction are presented in Sects. 4. 4.2 and 6.1. Here it suffices to mention that this three-component reaction affords P-amino carbonyl compounds known as Mannich bases. 

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