Mannich bases, preparation

Other modifications of the polyamines include limited addition of alkylene oxide to yield the corresponding hydroxyalkyl derivatives (225) and cyanoethylation of DETA or TETA, usuaHy by reaction with acrylonitrile [107-13-1/, to give derivatives providing longer pot Hfe and better wetting of glass (226). Also included are ketimines, made by the reaction of EDA with acetone for example. These derivatives can also be hydrogenated, as in the case of the equimolar adducts of DETA and methyl isobutyl ketone [108-10-1] or methyl isoamyl ketone [110-12-3] (221 or used as is to provide moisture cure performance. Mannich bases prepared from a phenol, formaldehyde and a polyamine are also used, such as the hardener prepared from cresol, DETA, and formaldehyde (228). Other modifications of polyamines for use as epoxy hardeners include reaction with aldehydes (229), epoxidized fatty nitriles (230), aromatic monoisocyanates (231), or propylene sulfide [1072-43-1] (232). 

The Mannich bases prepared in this way from the enolate of cyclohexanone are formed with a diastereoselectivity of 66-84%, but the configuration is not known. 

In addition to the side reactions mentioned above, deamination of Mannich bases can occur, especially at elevated temperature, to give a,p-unsaturated derivatives. This route of decomposition of Mannich bases has been exploited as a means of in situ generation of a,p-unsaturated ketones in the Michael reaction and for the direct synthesis of a,3-unsaturated ketones several reviews of the Mannich reaction have discussed aspects of these applications.Recently, a direct one-pot synthesis of a-methylene ketones has been reported involving condensation of ketones with formaldehyde and A -methylaniline tri-fluoroacetate in aptotic solvents. Also, a less direct method has been described in which Mannich bases prepared from 3-keto esters, formaldehyde and dimethylamine are subjected to quatemarization and thermal fragmentation to yield a-methylene ketones.This method is particularly useful for the regios-pecific synthesis of a-methylene ketones because the aminomethylation reaction always takes place at the most activated position flanked by the ketone and ester groups. 

Although connection of polyalkylene or poly(alkylene oxide) groups to the polyamine is most commonly by the succinimide linkage, a different linking group is employed in another important class of ashless dispersants— the Mannich bases. They are prepared on a commercial scale by reaction of an alkylphenol with formaldehyde and a polyamine (173—177). The alkyl and polyamine moieties are similar to those used in the succinimide products. 

Tetrahydro-y-carbolines may be prepared by an internal Mannich-type reaction between 2-j8-aminoethyhndoles and formaldehyde. Kebrle et al. prepared 27 by the reaction of 2-lithio-l-methyl-indole with A-benzyl-A-ethylaminoacetone followed by debenzyl-ation treatment of 27 with formaldehyde led to the formation of the tetrahydro-y-carboline 28. Similarly, when the quaternary salts (30) of the Mannich bases (29) are heated at 100°, 1,2,3,4-tetrahydro-y-carbohnium salts (31) are formed. 

In recent years a number of methods have been developed for the preparation of dialkyl(methylene)ammonium salts (Mannich reagents)and their use in Mannich-type condensation reactions under anhydrous conditions has improved the scope and efficiency of this important synthetic process. However, the orientation of the Mannich reaction may nevertheless be difficult to control. Apart from the work of the submitters, the preparation of isomer-ically pure Mannich bases has only been achieved by indircci... 

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. 

Poly(2,6-dimethyl-l,4-oxyphenylene) (poly(phenylene oxide), PPG) is a material widely used as high-performance engineering plastics, thanks to its excellent chemical and physical properties, e.g., a high 7 (ca. 210°C) and mechanically tough property. PPO was first prepared from 2,6-dimethylphenol monomer using a copper/amine catalyst system. 2,6-Dimethylphenol was also polymerized via HRP catalysis to give a polymer exclusively consisting of 1,4-oxyphenylene unit, while small amounts of Mannich-base and 3,5,3, 5 -tetramethyl-4,4 -diphenoquinone units are always contained in the chemically prepared PPO. 

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. 

The reaction between trialkylboranes and enones has found some interesting synthetic applications. An example is the preparation of prostaglandin precursors from exo-methylene cyclopentanone, generated in situ from a Mannich base. After dehydrogenation, a second conjugate addition of tri-octylborane was used to introduce the w-chain (Scheme 25) [70]. 

Amino-substituted (Mannich base) polymers can be prepared by reacting amide-containing polymers with formaldehyde and a suitable amine. Sugiyama and Kamogawa (16) treated PAM in aqueous solution with excess paraformaldehyde (50°C, lh) followed by excess dimethylamine (50°C, lh). This procedure gave 68% conversion to amine. Schiller and Suen (9) used a similar procedure with monomeric formaldehyde and various amines, but with excess PAM. Muller et al. (17) prepared monomeric amines from... 

Oxazolidin-5-ones (11.110) are structurally related to oxazolidines, combining the motifs of a lactone and an O-Mannich base. These derivatives have already been discussed in Sect. 8.7.5. However, they serve here as a transition to [3,1 ]benzoxazepin-4-ones as an example of potential prodrugs. Thus, [3,l]benzoxazepin-4-one derivatives (11.111, R = H or Me, R = H, Me, Et, or Ph) were prepared from diclofenac (11.112) [137]. These prodrugs were stable for at least a few hours in simulated gastric juice, but, when administered to rats elicited an anti-inflammatory response comparable to that of diclofenac. One compound (11.111, R = Me, R = Et) was even more active than diclofenac without producing the gastric mucosal injury (ulcers) caused in all rats by diclofenac itself. Here again, there was no indication of whether the mechanism of hydrolysis is chemical or enzymatic. 

Some cyclic AT-Mannich bases have also been reported, for example, the imidazolidin-4-ones (11.116) that were investigated as potential prodrugs of peptides (11.117) [141], The imidazolidin-4-ones, prepared by allowing the peptide to react with acetone under dehydrating conditions, are bases with pKa values of 3 - 4. For most of the derivatives, hydrolysis is spontaneous the protonated form (i.e., at pH < 2) reacts ca. 10 - 30 times slower than does the neutral form (pH > 6). Very large differences in reactivity were noted,... 

A method of synthesis which has been used generally in this series employed a Fischer reaction at an early stage to form the tetrahydrocarbazolone nucleus [59] (Scheme 7.2). We devised a second route employing the Fischer method in which the key intermediate was the cyclohexenone (22) (Scheme 7.3). This was readily prepared by treating the enolate of the methyl enol ether (21) with dimethyl(methylene)ammonium iodide [60] to form the Mannich base which was then condensed with 2-methylimidazole to give (22). 

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. 

Entries 1 and 2 in Scheme 2.11 show the preparation of Mannich bases from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as bis(dimethylamino)methane in entry 3. On treatment with trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive electrophile. 

Terminal allenes.1 Terminal acetylenes can be converted by a one-step reaction into terminal allenes by treatment with formaldehyde, diisopropylaminc, and copper(l) bromide in refluxing THF or dioxane. The Mannich base is an intermediate, but, surprisingly, preparation of the quaternary base is not necessary. The source of the introduced hydrogen is not clear. The highest yields are obtained with 2-propynylic alcohols, ethers, and esters. 

The Mannich reaction, however, is an easily accomplished substitution, occurring in the 1- and 3-positions. The biological activity of numerous Mannich bases of indolizines has been investigated. The 1-substituted indolizines (34) and (35), which have been prepared using a Mannich reaction, may serve as examples (Scheme 6). 

Several dehydro Mannich bases have been prepared in a similar way. The reaction between 1,3,5-triazine, morpholine, and diethyl malonate is a typical example (Scheme 13) (76T2603). 

Ethylene-Based (C-2> Routes. MMA and MAA can be produced from ethylene as a feedstock via propanol, propionic acid, or melhyl propionate as intermediates. Propanal may be prepared by hydrofonnylalion of ethylene over cobalt or rhodium catalysts. The propanal then reads in the liquid phase with formaldehyde in the presence of a secondary amine and. optionally, a carboxylic acid. The reaction presumably proceeds via a Mannich base intermediate which is cracked to yield methacrolcin. Alternatively, a gas-phase, crossed akin I reaelion with formaldehyde cataly zed by molecular sieves [Pg.988]

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 forward synthetic sequence would therefore involve the Michael reaction of 2-methylcyclopentane-l,3-dione with methyl vinyl ketone to give (20), followed by cyclisation to the hydroxyketone (19), and then dehydration to the target molecule (13a). The overall process of addition and cyclisation is known as the Robinson annelation reaction.3 In this preparative example (Expt 7.6) the methyl vinyl ketone is used directly under conditions which minimise its polymerisation 48 it should be noted, however, that many literature examples of the annelation reaction use Mannich bases or the corresponding methiodides as an in situ source of the a, /J-unsaturated carbonyl component (see Section 5.18.2, p. 801). 

R-CONH2+ CI-I20+ HNR,R2 = R-CONH-CH2-NR1R2+ H,0 FIGURE 16.2 Schematic for preparation N-Mannich base prodrugs. 

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