Mannich bases reaction, with active

Imines are more versatile than preformed iminium salts in reactions with active methylene compounds because the product, a secondary Mannich base, has an additional site on the nitrogen for further elaboration (equation 11). Imine condensation reactions are also superior to the classical method for the synthesis of secondary Mannich bases because cross-condensation reactions do not occur, due to the absence of free aldehyde in solution. The major side reactions occurring in imine condensation reactions are abstraction of enolizable ot-protons and self-condensation reactions of enolizable imines at elevated temperature. 

For the reaction of the 3-pyridine aldimine 16e, the first equivalent of zinc chloride is coordinated to the more nucleophilic pyridine nitrogen and thus is inactivated. Only the second equivalent activates the imine. However, the zinc chloride coordinated to the more nucleophilic pyridine nitrogen, logically exposes more nucleophilic chlorine ligands for the interaction with the silyl dienol ether 19. Therefore, in this case the nucleophile 19 is introduced from the free back side of 16e (Formula C) and furnishes selectively the Mannich base 28 with opposite stereochemistry compared to the compounds 27. 

Sulphone syntheses based upon sulphinic acids include addition to activated alkenes, " condensation of salts RSOz Na" with Mannich bases or with an aldehyde and a urea or a thiourea in a Mannich-type reaction, and reaction with a diazoalkane benzhydryl p-tolyl sulphone is formed... 

The Mannich reaction consists in the condensation of formaldehyde with ammonia or a primary or a secondary amine and a compound containing at least one hydrogen atom of pronounced reactivity the active hydrogen atom may be derived from a methylene group activated by a neighbouring keto group, or from a nitroparaffin, or it may be the o- or p-hydrogen atoms in phenols. Thus when acetophenone is boiled in alcoholic solution with formaldehyde and dimethylamine hydrochloride, the Mannich base P-dimethylamino-propiopbenone hydrochloride (I) is readily formed ... 

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]. 

The Mannich reaction consists on the condensation of a CH-activated compound with a primary or a secondary amine and a non-enolizable aldehyde or ketone to afford p-aminocarbonyl derivatives known as Mannich bases (Scheme 20). This sequence is of great use for the constmction of heterocyclic targets, as illustrated for example by the Robinson-Schopf synthesis of tropinone in 1937 or by the preparation of some azabicyclo[3.3.1]nonanones or pyranocoumarine derivatives (Fig. 1) [100]. In the following, representative recent examples of the formation of five- to seven-membered ring heterocycles will be presented. 

A Mannich reaction is the reaction of formaldehyde with a primary or secondary amine and a compound with an active hydrogen atom. The product, an amine with a y-carbonyl, is called a Mannich base, useful in a number of synthesis reactions. An example is in Figure 15-23, and the mechanism is in Figure 15-24. 

The nature of the aromatic substituents is apparently not critical for SSRI activity, as indicated by the structure of duloxetine (23-5), where one ring is replaced by thiophene and the other by naphthalene. The synthesis starts as above by the formation of the Mannich base (23-1) from 1-acetyl thiophene with formaldehyde and dimethyl-amine. Treatment of that intermediate with the complex from lithium aluminum hydride and the 2R,3S entantiomer of dimethylamino-l,2-diphenyl-3-methyl-butane-2-ol gives the S isomer (23-2) in high enantiomeric excess. Treatment of the aUcoxide from (23-2) and sodium hydride with 1-fluoronaphthalene leads to the displacement of halogen and thus the formation of ether (23-2). The surplus methyl group is then removed by yet another variant of the von Braun reaction that avoids the use of a base for saponifying the intermediate urethane. Thus, reaction of (23-3) with trichloroethyl formate leads to the A -demethylated chlorinated urethane (23-4). Treatment of that intermediate with zinc leads to a loss of the carbamate and the formation of the free secondary amine duloxetine (23-5) [23]. 

The compounds obtained by the replacement of ring sulfur by carbon, as in the case of penicillins, show somewhat improved antibiotic properties. A free radical— based route has been described for the conversion of fermentation derived cephalosporins to their carbocyclic derivatives. The first step in this sequence consists of the condensation of the cephalosporin sulfone (36-1) with formaldehyde and dimethyla-mine the initial product from the Mannich-like reaction consists of the exomethylene derivative at the position adjacent to the activating sulfone. The product is treated in situ with phenylselenol to give the Michael adduct (36-2). This fragments with an extmsion of sulfur dioxide when heated with the free radical initiator AIBN in the presence of tributyltin hydride the reaction can be envisaged as leading to the... 

Richter et al. prepared /V-benzoyl-/V -(/V-aryloxamoyl) ureas 138 (R = Ph R = H, Me) by using a sequence of reactions involving ben-zoylation, reaction with oxalyl chloride, and, finally, reaction with anilines (Scheme 5) (78JOC4150). Karparov et al. found, in broad-spectrum antiviral screening, that Mannich bases 139 (m = 4,5) showed some activity, but that the parent urea (104) and thiourea (105) did not (84AF9). However, a later study revealed the two Mannich bases were inactive toward alphavi-rus models (86MI1). 

The reaction of an amine with, principally, formaldehyde, followed by further reaction with compounds having active hydrogen atoms, give rise to the Mannich bases which are discussed in Sections 5.18.2, p. 801, and 6.12.7, p. 1050. 

Under appropriate conditions activated thiazoles are alkylated at the 5-position 2-amino 4-methylthiazole is alkylated in the 5-position by heating with /-butyl alcohol in sulfuric acid (24). Under similar conditions 4-methyl-2-phenylthiazole is alkylated by cyclohexanol. 2-Acetylamino-4-methylthiazole reacts with dimethylamine and formaldehyde to afford the corresponding Mannich base (25). 2-Hydroxy-4-methyIthiazole fails to react when submitted to Friedel-Crafts benzoylation conditions whereas it reacts normally in Gatter-mann and in Reimer-Tiemann formylation reactions yielding the 5-formyl derivative (26). 2,4-Dimethylthiazole undergoes perfluoroalkylation when heated at 200 °C for 8 h in a sealed tube with perfluoropropyl iodide and sodium acetate (27). 

Thus many compounds arc obtained (250, Table 24), which may be considered to be derived from C-alkylation of the nucleophilic reagent by the Mannich base. Alkyl ketonic and phenolic bases arc mostly involved in this reaction, which exhibits many analogies with aminomethylation, particularly concerning chemo- and regioselectivity on aromatic and heteroaromatic derivatives. Ring activation by means of hydroxy and amino substituents in the alkylation of pyridine and pyrimidine derivatives is also required. 

A very wide range of Mannich bases can be subjected to replacement reaction with —SH derivatives, including ketobases producing optically active y-ketosulfides [275, R = PhCO-CH(Me) , when the reaction is carried out in the presence of catalytic amounts of chiral amine of the cinchonidinc type. ... 

When a Mannich reaction is carried out between a substrate containing at least two active hydrogen atoms and a primary or a bis-secondary amine, a polycondensation takes place with production of a polymeric derivative. Fhe polycondensation can also occur when both an NH group and one active hydrogen atom arc present in the same molecule. The reaction product is thus characterized by the presence of the methylene moiety, whieh is derived from the formaldehyde, and forms the polymer backbone, with the consequent possibility of polymer degradation by deamination or dcaminomethy-lation both of these reactions are typical of Mannich bases (Chap. II, A). 

The chemical behavior of phenolic compounds 418 in the crosslinking is related to replacement of the amino group by the activated aromatic ring. Other nucleophilic compounds may give this reaction (see below). A significant example is afforded by the reaction of the oligomeric Mannich base 423 (Fig. 161), which, upon being heated to 210° C, releases dimethylamine with formation of the cros.slinked resin 424. ... 

Chiral amines, also employed in the synthesis of perhydro-oxazepines and y-diaze-pines, have been used for the preparation of asymmetric P-Mannich bases such as the derivatives 102, which exhibit the contemporary presence of optically active P and amino group. The synthesis involves reaction of the hydroxymethyl derivative of the substrate with the chiral amine. ... 

Most of the poly functional substrates belonging to this group of compounds have two (or more) active hydrogen atoms located on different positions of the molecule. Thus, in the case of symmetrical substrate with two identical reactive XH groups 109, the Mannich bases 110-115 (Rg. 42) arc obtained by reaction of the. substrate with formaldehyde and amine in the molar ratio 123. 

Porphyrin synthesis and functionalization based on the chemistry of Mannich bases, briefly mentioned in previous chapters, are recalled here. As far as porphyrin synthesis is concerned, studies of biomimetic models of photochemically active reaction centers are worth noting. The synthetic procedure involves amino group replacement of the pyrrole bis-Mannich base with formation of the tetrapyrrole ring of porphyrin (see 360, Chap. 11). 

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