Mannich direct

Overman et al. have applied their now well-established Mannich-directed cationic aza-Cope rearrangement strategy to octahydroindolones (86), and also to a short synthesis of the amaryllidaceae alkaloid ( )-crinane (87). ... 

These results contrasted sharply with those obtained with a HHT that was relatively unstable to the reaction conditions. For example, the commercially available HHT of glycinonitrile 28 gave a very poor yield (6%) of coupled glyphosate product with diethyl phosphite because the reaction must be run with acid-catalysis at much lower temperatures (27,38). Somewhat higher yields were observed when 28 was used directly under the modified, acidic Mannich conditions to provide iV-phosphonomethylglycinonitrile 29, which was hydrolyzed direedy to GLYNa3 (39). 

The less highly substituted Mannich bases can also be prepared directly from ketones and dimethyl(methylene)ammonium trifluoroacetate by the procedure reported here, which takes advantage of the isomerization of Mannich bases in trifluoroacetic acid. (In acetic acid the Mannich bases undergo elimination of dimethylamine to give a-methylene ketones.) This method is rapid and affords products having an isomeric purity of at least 90% without difficult separations. The 49-57% yield of l-(di-methylamino)-4-methyl-3-pentanone obtained with this procedure compares favorably with the overall yields of amino ketones prepared by the indirect routes mentioned previously. 

Scheme 2.12 shows some representative Mannich reactions. Entries 1 and 2 show the preparation of typical Mannich bases from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as l>is-(di methyl ami no)methane in Entry 3. On treatment with trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive electrophile. lV,A-(Dimethyl)methylene ammonium iodide is commercially available and is known as Eschenmoser s salt.192 This compound is sufficiently electrophilic to react directly with silyl enol ethers in neutral solution.183 The reagent can be added to a solution of an enolate or enolate precursor, which permits the reaction to be carried out under nonacidic conditions. Entries 4 and 5 illustrate the preparation of Mannich bases using Eschenmoser s salt in reactions with preformed enolates. 

More recently, asymmetric Mannich-type reactions have been studied in aqueous conditions. Barbas and co-worker reported a direct amino acid catalyzed asymmetric aldol and Mannich-type reactions that can tolerate small amounts of water (<4 vol%).53 Kobayashi found that a diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF2, a chiral diamine ligand, and trifluoromethanesul-fonic acid (Eq. 11.31).54 The diastereoselective Mannich-type reaction... 

The wide latitude of structural variation consistent with bioactivity in this series is illustrated by the observation that antiinflammatory activity is maintained even when the second aromatic group is attached directly to the pyrrole nitrogen rather than to the heterocyclic ring via a carbonyl group as in the previous case. Condensation of p-chloroaniline with hexane-2,5-dione (or its dimethoxy-tetrahydrofuran equivalent) affords pyrrole 7. The acetic acid side chain is then elaborated as above. Thus, Mannich reaction leads to the dimethylaminomethyl derivative 8, which is in turn methylated (9) the quaternary nitrogen replaced by cyanide to afford 10. Hydrolysis of the nitrile then gives clopirac (11). 

Catalytic amounts of I fCl4-AgC104 and Hf(OTf)4 are used for activation of acid halides and acid anhydrides for Friedel -Crafts acylation (Scheme 42) 178 the reactions of both reactive and unreactive aromatic substrates proceed smoothly in the presence of Hf(OTf)4. Furthermore, the Fries rearrangement179,180 and direct C-acylation of phenolic compounds181,182 take place using Hf(OTf)4. Formation of esters and Mannich-type reactions and allylation of imines have been also reported.152... 

Recently, novel bifunctionalized zinc catalysts have been developed (compounds (N) and (P), Scheme 55). They have both Lewis-acid and Lewis-base centers in their complexes, and show remarkable catalytic activity in direct aldol reactions.233-236 A Zn11 chiral diamine complex effectively catalyzes Mannich-type reactions of acylhydrazones in aqueous media to afford the corresponding adducts in high yields and selectivities (Scheme 56).237 This is the first example of catalytic asymmetric Mannich-type reactions in aqueous media, and it is remarkable that this chiral Zn11 complex is stable in aqueous media. 

Moedritzer, K. and Irani, R.R., The direct synthesis of a-aminomethylphos-phonic acids. Mannich-type reactions with orthophosphorous acid, /. Org. Chem., 31, 1603, 1966. 

Sodeoka and co-workers have reported enantioselective aldol and Mannich reactions (Equations (106) and (J07)) 464,464a 464e Involvement of palladium enolates was confirmed by 111 NMR and ESI-MS spectrometry. /3-Keto esters (pronucleophiles) directly add to imines with high selectivity without preformation of silicon enolates (Equation (108)). 

In addition, quite recently a direct catalytic asymmetric Mannich-type reaction has been achieved by the cooperative catalysis of ALB and La(0Tf)3-nH20. 

Cyclic. S -Mannich bases are rarely encountered in medicinal chemistry. The (R)-thiazolidine-4-carboxylic acids (11.113, Fig. 11.15), which are used as derivatives and chemical delivery systems for L-cysteine (11.114), provide an excellent example of S-Mannich bases. These compounds underwent activation by two distinct mechanisms, directly by nonenzymatic hydrolysis to cysteine and the original aldehyde (Fig. 11.15, Pathway a), and oxidatively (Pathway b) [138]. The latter route involved first oxidation by mitochondrial enzymes to the (f )-4,5-dihydrothiazole-4-carboxylic acid (11.115), followed by (presumably nonenzymatic) hydrolysis to /V-acylcysleine, and, finally, cytosolic hydrolysis to cysteine (11.114). 

Alkyl-3-hydroxy-4-pyridinones can be converted into analogues containing, e.g., anilino-, phenylthio-, or 2-hydroxyethylthio-substitu-ents by silver(I) oxidation (Ag20 in ethanol) followed by Michael addition (71). In aminomethylation of 3-hydroxy-4- and -2-pyridinones under Mannich conditions the position of substitution can be tailored, by reaction conditions to position C4 or C6, or by converting the OH into OMe, which directs substitution to C5 (72). 

In the direct associative approach, which is applied in the case of relatively simple molecules, the chemist directly recognises within the structure of the target molecule a number of readily available structural subunits which can be properly joined, by using standard reactions with which he is very familiar. For instance, it is easy to see that structure 1 can be obtained by bringing together, the fragments a, b and c, in a Mannich condensation ... 

Due to environmental concerns, research efforts have been directed toward the replacement of chromate-based post-treatments. This paper focuses on a new unique chromium free post-treatment based on "Mannich derivatives" of po1y-viny1pheno 1 which have demonstrated excellent performance on both zinc and iron phosphate treatments. 

A second, even more worrying problem is the side reaction, the formation of condensation products. This process is essentially irreversible in most cases. The condensation products can arise either from the aldol product or directly through a Knoevenagel-Mannich type reaction where the enamine reacts with an imininm ion [26, 81, 82]. The condensation process requires only an external Brpnsted acid, whereas the aldol process appears to require simultaneous activation of the carbonyl electrophile by an internal Brpnsted acid/hydrogen bond donor (Scheme 15). 

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

Cordova has also shown hydrogen peroxide to be an effective oxidant in the epoxidation of a,P-unsatnrated aldehydes using diarylprolinol ether 30 as the catalyst (Fig. 9) [146, 147], Within these reports it was also shown that the resulting epoxy aldehydes could be used directly in either Wittig or Mannich reactions, providing synthetically useful one-pot protocols to prepare densely functionalised building blocks for further elaboration. 

Terada et al. found the direct Mannich reaction between iV-Boc-protected aldi-mines 11 and acetyl acetone (12) to be catalyzed by different phosphoric acids 3 (Scheme 6). Varying the aromatic groups at the 3,3 -positions influenced the yields slightly (88-99%), but the enantioselectivities to a high degree (12-95% ee). 

The full potential of this C-H activation process, as a surrogate Mannich reaction, was realized in the direct asymmetric synthesis of threo-methylphenidate (Ritalin) 217 (Eq. 28) [140]. C-H insertion of N-Boc-piperidine 216 using second-generation Rh2-(S-biDOSP)2 and methyl phenyldiazoacetate resulted in a 71 29 diastereomeric mixture, where the desired threo-diastereomer was obtained in 52% yield with 86% enantiomeric excess. Winkler and co-workers screened several dirhodium tetracarboxami-dates and found Rh2(R-MEPY)4 to be the catalyst that gives the highest diastereoselec-tivity for this reaction [142]. 

Cordova A (2004) The direct catalytic asymmetric cross-Mannich reaction a highly enantio-selective route to 3-amino alcohols and alpha-amino acid derivatives. Chem Eur J 10 (8) 1987-1997... 

List B (2000) The direct catalytic asymmetric three-component Mannich reaction. J Am Chem Soc 122(38) 9336-9337... 

Notz W, Tanaka F, Barbas CF (2004) Enamine-based organocatalysis with proline and diamines the development of direct catalytic asymmetric aldol, Mannich, Michael, and Diels-Alder reactions. Acc Chem Res 37(8) 580-591... 

In one of the few publications not directly connected with the synthesis of alkaloids, an original method for the formation of hexahydroazocino[4,3-fc]-indoles using a Mannich intermolecular reaction of the corresponding 2-(N-i -aminobutyl)indoles 50 has been reported (Scheme 14 87JCS(P1)1599). 

Bicyclic ester 100 forms in analogy to isomeric ester 65 (Section 2.4.1.1) (07JOC5608). /l-Phenylethylamine 101 undergoes palladium-catalyzed direct aromatic carbonylation, thus providing another synthesis of benzo-lactam 78b (06JOC5951). A stereoselective nitro-Mannich/lactamization cascade of y-nitro ester and cyclic imine affords polysubstituted lactam 102 (08OL4267). 

Surprisingly, 3-(2-dialkylaminoethyl)-l,2-benzisoxazoles 207 can be easily obtained by direct cyclization of the corresponding Mannich bases oxime acetates 206 in refluxing benzene in the presence of anhydrous K2CO3 (equation 90). The known methods for ring closure to 1,2-benzisoxazole were ineffective for this class of pharmacologically relevant compounds . 

The dimethylaminomethyl group (entry 9) is easily introduced by a Mannich reaction, and lithiation occurs readily at -78°C (88JOC5685). After reaction with a variety of electrophiles, hydrolysis can be performed directly with aqueous acid to give 2-substituted imidazoles in good yield. However, the 2-lithio anion 47 was found to be quite basic, despite the base-weakening effect of coordination with the amino substituent, and thus it was capable of deprotonating the 2-butyl derivative 48 as it was formed by reaction with 1-bromobutane (Scheme 42). No such side-reac-... 

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