Amines from Mannich bases

These reactions have a general relevance in organic synthesis, as they allow the performance of X-methylation reactions such as cyano-, thio-, amidomethylations, etc. starting from hydrogen cyanide, amides, etc. When, in particular, the abovemen-tioned methylol derivatives are allowed to react with amine (R —YH = primary or secondary amine), a Mannich base is produced. 

SoHman et al. reported the synthesis of 3-triphenylphosphoranylidene-chromanes 117 from Mannich bases 115 of the commercial moUusddde niclosamide and the ciunulated yhdes 2, 82 or 88 [73]. The reaction was carried out in boihng toluene and is thought to proceed by initial addition to give the acyl ylides 116, which then cycHze by the unusual expulsion of a secondary amine, i.e. by nudeophihc attack of the ylidic carbon atom at the benzyhc carbon atom. Intermediates 116 were not isolated. The moUusdddal activities of compounds 117 were found to be about tenfold lower than that of the parent niclosamide (Scheme 25). 

Highly frmctionalized heterocycles could be assembled using an organocatalytic, asymmetric variation of the Mannich reaction. Cyclic urea 130 could be generated from Mannich base 129. This compound was accessible by the reaction of 127 and 128 catalyzed by the chiral amine 129. 

Primary nitroparaffins react with two moles of formaldehyde and two moles of amines to yield 2-nitro-l,3-propanediamines. With excess formaldehyde, Mannich bases from primary nitroparaffins and primary amines can react further to give nitro-substituted cycHc derivatives, such as tetrahydro-l,3-oxa2iaes or hexahydropyrimidines (38,39). Pyrolysis of salts of Mannich bases, particularly of the boron trifluoride complex (40), yields nitro olefins by loss of the amine moiety. Closely related to the Mannich reaction is the formation of sodium 2-nitrobutane-1-sulfonate [76794-27-9] by warming 1-nitropropane with formaldehyde and sodium sulfite (41). 

With amine initiators the so-called self-catalysed polyols are obtained, which are used in the formulation of rigid spray foam systems. The rigidity or stiffness of a foam is increased by aromatic initiators, such as Mannich bases derived from phenol, phenoHc resins, toluenediamine, or methylenedianiline... 

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. 

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 ... 

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. 

Rosenau, T. Mereiter, K. Jager, C. Schmid, P Kosma, P. Sulfonium ylides derived from 2-hydroxy-benzoquinones crystal and molecular structure and their one-step conversion into Mannich bases by amine A-oxides. Tetrahedron 2004, 60(27), 5719-5723. 

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... 

Mannich bases derived from polynitroalkanes are usually unstable because of the facile reverse reaction leading to stabilized nitronate anions. The nitration of Mannich bases to nitramines enhances their stability by reducing the electron density on the amine nitrogen through delocalization with the nitro group. The nitration of Mannich bases has been exploited for the synthesis of numerous explosives, some containing both C-NO2 and N-NO2 functionality. Three such compounds, (163), (164) and (165), are illustrated below and others are discussed in Section 6.10. 

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. 

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]. 

There are several classes of alkaloids. Among these are purines such as xanthine and caffeine, ter-penes (Chapter 22), polyketides (Chapter 21), and alkaloids derived from amino acids. The basic amino acids ornithine, arginine, histidine, and lysine as well as the aromatic amino acids, anthranilate, and nicoti-nate are some of the starting materials.199 201 Robinson202 203 in 1917 recognized that many alkaloids are derived directly from aromatic amino acids. He proposed that alkaloids arise from Mannich reactions (Eq. 25-12) in which an amine and an aldehyde (probably through a Schiff base) react with a nucleophilic carbon such as that of an enolate anion. Many of the... 

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]

The elimination reaction can be followed only for pH > (pKvm — 2). The rate of the side reaction of the a,(i-unsaturated ketone increases with increasing pH and for phenylvinyl ketone becomes of importance at pH values above about 9. To study the elimination process unaffected by the hydration of the a,[3-unsaturated ketone generated, it was necessary to find a Mannich base the elimination of which would take place at pH << 9, i.e. with a.pKjtB 9. 3-Morpholinopropiophenone proved to be a suitable model (27) this compound has a pK B value of 6.8, so that constants ke and kaa at pH < 9 can be quantitatively evaluated without any effect from cleavage of the a,(3-unsaturated ketone. The validity of the kinetic equations corresponding to scheme (13) was proved both for the elimination of p-aminoketones (27) and for the addition of primary and secondary amines to a, (3-unsaturated ketones (28). 

The conversion of nitrocoumarins into the amino compounds has been achieved by hydrogen transfer (95JCR(S)372) and an intramolecular hydride transfer features in the formation of Mannich bases of 4-aminocoumarins from 4-alkylaminocoumarin-3-carbaldehyde (95S633). Amine derivatives of coumarin-3-carboxaldehyde undergo a thermal 1,3-cycloaddilion involving an oxime nitrone isomerisation on reaction with Al-methyl-hydtoxylamine yielding hetero-fused coumarins (95JCS(P1)1857). 

The Mannich reaction of an aldehyde enol (example Formula C in Figure 12.14) or a ketonic enol (example Formula C in Figure 12.15) often proceeds beyond the hydrochloride of a /l-aminocarbonyl compound or the Mannich base. The reason is that the secondary amine or its hydrochloride, which has previously been incorporated as part of the iminium ion, is relatively easy to eliminate from these two types of product. The elimination product is an a,fi-unsaturated aldehyde (example Formula E in Figure 12.14) or an a,/l-unsaturated ketone (example Formula D in Figure 12.15)—that is, an a,/l-unsaturated carbowyl compound. Figure 13.51 will show how the Mannich reaction of a carboxylated lactonic enol provides access to an a-methylene lactone, that is, an a,/l-unsaturated carboxyl compound. 

Tfce preferred synthetic route to these important intermediates is the Mannich reaction (Chapter 27), The compound is stored as the stable Mannich base and the unstable enone released by elimination of a tertiary amine with mild base, The same conditions are right for this elimination and for conjugate addition, Thus the aw-methylene compounds can be formed in the flask for immediate reaction with the enol(ate) nucleophile, The overall reaction from (3-amino carbonyl to 1,5-dicarbonyl appears to be a substitution but the actual mechanism involves elimination and conjugate addition,... 

Either the tertiary amine or the quaternary ammonium salt can be stored as a stable equivalent of the exo-methylene compound. In our first example, the Mannich base with dimethylamine is first methylated with methyl iodide and then added to the conjugate addition reaction. Elimination of trimethylamine, which escapes from the refluxing ethanol as a gas, reveals the exo-methylene ketone in which the methylene group is exo to a chain. Fast conjugate addition of the stabilized enolate of diethyl malonate produces the product. 

First of all, the steric hindrance may seriou,sly affect yield and/or stability of the product, when bulky substituents arc bound to the amine rcagent. Second, complications may arise, as we have seen before, with polyfunctional amines, mainly ammonia and primary amines, due to the pos.sibilily that the unrcacted hydrogen atoms of the amine may undergo further reaction with formaldehyde, thus producing undesired by-products. Similarly, the use of secondary bifunctional amines, such as piperazine, always leads to a bis-Mannich base, due to reaction of both amino groups. Attempts to limit the reaction to only one amine function, as well as hydrolysis of the Mannich product obtained from aminomethylation of mono-N-acylpiperazines, invariably gives the di.substituted piperazine 23. ... 

Harrcl, W. B., Mannich bases from 1.2-di-phcnylindolizine ephedrinc and mclham-phctaminc as amine componeni.s, J. Pharm. S< i.. 59. 275. 1970. 

Craig, J. C., Johns, S. R., and Moyle. M., Amine exchange reactions. Mannich bases from primary aliphatic amines and firom amino acids, J. Org. Chem., 28, 2779, 1963. 

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). 

Various types of bis-Mannich bases (Table 32), ranging from kctonic to phenolic and amidic, are suitable for condensation with bis-amines and bis-thiols. As far as bis-amines are eoncemed, besides the compounds 379-381 of Table 31, methylpiperazine 404 is used. An even larger number of bis-thiols (405-409) arc employed in the synthesis of polythioethers. 

Dimethylamino Mannich bases arc the preferred starting material, as they release volatile dimcthylaminc, which is easily removed from the reaction mixture. The corresponding quaternary ammonium salts also have been employed, and good results are obtained by using the hydrochloride of the base in aprotic medium, since the by-product of condensation is in this case an insoluble amine hydrochloride, which is thus subtracted from the equilibrium. ... 

Molecules of type I are the classical product of reactions between monofunctional reactants. In many cases, they can be considered to be derived from the functionalization of a substrate or, reciprocally, of an amine, in order to attach chemical moieties purposely designed for specific uses, without substantially affecting the essential molecular structure. This is the case, for instance, of the antibiotic substance 494, which assumes hydrophilic properties upon aminomethylation of the pharmacologically active substrate having an amino acidic residue, or of the complexant agent 495,- as well as of the polyacrylamide Mannich base 502. - ... 

Synunetrically disubstituted molecules of type II are mostly obtained from bifunctional substrates such as bisphenols, cyclic urcids, etc., or bifiinctional amines such as ethylenediamine or piperazine. Accordingly, the amino group replacement of mono-functional Mannich bases by bifunctional nucleophiles such as nitroalkanes or bisamides gives derivatives of type II, as represented by the heat stabilizer for polymers 496, bearing two antioxidant phenolic moieties per molecule. 

---