Mannich bases quaternary ammonium salts

Methyl vinyl ketone 2 tends to polymerize, especially in the presence of a strong base the yield of annulation product is therefore often low. A methyl vinyl ketone precursor, e.g. 6, is often employed, from which the Michael acceptor 2 is generated in situ, upon treatment with a base. The quaternary ammonium salt 6 can be obtained by reaction of the tertiary amine 5, which in turn is prepared from acetone, formaldehyde and diethylamine in a Mannich reaction. 

Trimerization to isocyanurates (Scheme 4.14) is commonly used as a method for modifying the physical properties of both raw materials and polymeric products. For example, trimerization of aliphatic isocyanates is used to increase monomer functionality and reduce volatility (Section 4.2.2). This is especially important in raw materials for coatings applications where higher functionality is needed for crosslinking and decreased volatility is essential to reduce VOCs. Another application is rigid isocyanurate foams for insulation and structural support (Section 4.1.1) where trimerization is utilized to increase thermal stability and reduce combustibility and smoke formation. Effective trimer catalysts include potassium salts of carboxylic acids and quaternary ammonium salts for aliphatic isocyanates and Mannich bases for aromatic isocyanates. 

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. 

Five-membered O-heterocycIic derivatives of the type dihydrobenzofuran (352 in Fig. 137) are formed by reaction with diazomethane or analogous reagents. It is to be stressed, in partieular, that the deamination of a Mannich base may be favored by the formation of amine N-oxide, instead of the corresponding quaternary ammonium salt, as is usually required. 

Yamada, K., Itoh, N., and Iwakuma. T., One-pot conversion of Mannich bases via quaternary ammonium salts into the corresponding methyl compounds with sodium cyanoboro-hydride in HMPA, J. Chem. Soc. Chem. Commun.. 1089, 1978. 

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. ... 

Steroidal aminomethyl derivatives have been subjected to some of the reactions typical of Mannich bases, described in Chap. II, usually with the aim of introducing structural modifications of the molecule by means, in particular, of deamination and hydrogen-olysis. The formation of a quaternary ammonium salt (mainly iodomethylatc) by N-alkylation of the base - is also performed to the same end in order to obtain unsaturated deaminated products. ... 

Photography—Several types of Mannich bases and derivatives are employed in this field. 599 Crosslinking agents derived from piperazine (534, Sec. A.2) are hardeners for gelatin photographic emulsions, and O-aminomethyl derivatives of piperazine, used under the form of polymeric quaternary ammonium salts 599, are useful as sensitizers for photographic emulsions. ... 

Except in rare cases, the deamination reaction (Fig. 85) is peculiar to C-Mannich bases and involves the elimination of a primary or secondary amine from 231 or of a tertiary amine from the quaternary ammonium salt 232. The presence of a hydrogen atom in the P position with respect to the amino group is not essential, as other groups, such as the carboxyl group of P-amino acids 233 may also be eliminated in conjunction with the amine. 

Several different deamination procedures are reported in Table 23, as the reaction may take place alternatively by modification of Mannich synthesis (A), by suitable treatment of a Mannich base (B), or by conversion of the base into the corresponding quaternary ammonium salt, which is more easily decompo,sable (C). Due probably to steric reasons, some particular amines, such as diethylamine, are more suited to the deamination process. - - - ... 

As reported in Tabic 28, hydrogcnolysis is performed only on C-Mannich bases, usually as quaternary ammonium salts, employing hydrogen or metal hydride. 

N-Alkylation—Secondary Mannich bases can give the corresponding tertiary derivatives by treatment with particular alkylation agents, such as epoxides (affording P-ami-noalcohols) and acrylic derivatives. Tertiary Mannich bases, mostly, are submitted to N-alkylation in order to produce stable quaternary ammonium salts to be subsequently subjected to deamination (Sec. A.2). However, different quaternary ammonium byproducts can be readily given by the reaction. " For instance, a base-catalyzed rearrangement is afforded by allyl ammonium salts 365 (Fig. 144), obtained by N-alkylation of acetylenic Mannich bases with ally] halides. " In the presence of sodium hydride, the compounds 365 yield a wide range of 3-amino-5-hexen-l-yne derivatives 366. 

Saheki. Y.. Kimura, M., and Negoro, K., Meashutkin reaction of Mannich bases derived from p-cresol and antimicrobial activities of their quaternary ammonium. salts, Nippon Kaguku Kaishi. 1123, 1978 Chem. Ahstr.. 89, 163167, 1978. 

Among N-Mannich bases, derivatives of polyacrylamide (517) are investigated particularly for their flocculant properties in water treatment. The corresponding quaternary ammonium salts are also used. Benzimidazolic and bcnzotriazolic Mannich bases 518, usually with the bulky alkyl group linked to the amine moiety, are used effectively against corrosion in a manner similar to alkylphenols 513, which have the apolar group linked to the substrate moiety. 

Reduction of —CH2N(CH3)i to —CH3 The quaternary ammonium salts of Mannich bases are reduced to the corresponding methyl compounds by NaBHaCN in HMPT. 

In addition to the Mannich reaction being a valuable method for preparing amino ketones,which are encountered in many drugs, the reaction is also important in organic synthesis in providing a stable equivalent of a conjugated exo-methylene moiety. Thus, addition of methyl iodide to the Mannich base converts it to the quaternary ammonium salt. Subsequent treatment with a base results in a [3-elimination of trimethylamine to generate the a-methylene ketone. 

An alternative method for the formation of an a,(3-unsaturated carbonyl compound is the elimination of an initially formed Mannich product. The procedure is particularly effective for the formation of (3,(3-bis(unsubstituted) a, -unsaturated carbonyl compounds. The Mannich product 11 can be formed in the presence of a secondary amine and a non-enolizable aldehyde such as formaldehyde (2.12). The Mannich reaction is a useful carbon-carbon bond-forming reaction and the products have found application in the synthesis of, in particular, alkaloid ring systems. The Mannich product may eliminate under the reaction conditions, or can be alkylated to form the quaternary ammonium salt in order to induce elimination. A convenient variation of this method is the use of Eschenmoser s salt, H2C=NMe2 X. For example, Nicolaou s synthesis of hemibrevetoxin B used this salt in order to introduce the required methylene unit a- to the aldehyde 12 (2.13). The same transformation with the corresponding methyl ester, which is less acidic, requires prior enolization with a strong base (e.g. NaN(SiMe3)2) and subsequent quatemization of the tertiary amine with iodomethane and elimination using DBU. 

Pyrrole Mannich bases have been transformed into the tertiary ammonium salt as a good leaving group. Therefore, treatment of the quaternary ammonium salt with sodium sulfinate to give the corresponding sulfonyl pyrrole, which in turn, could undergo another Mannich reaction to synthesize sulfonyl pyrrole Mannich bases as germicides. ... 

The P-dialkylamino ketone product, known as a Mannich base, can undergo an elimination reaction upon heating to afford an a,P-unsaturated ketone. Alternatively, treatment of a P-amino ketone with an excess of methyl iodide gives a quaternary ammonium salt that can be eliminated with base (Hofmann elimination). 

Practical laboratory synthesis of vinyl ketones starts with the preparation of (3-amino ketones Mannich bases) and then quatemization of the terf-amino group followed by thermal degradation of the quaternary ammonium salt (Scheme 4.36). 

There are undoubtedly many early examples of the phenomenon now known as phase transfer catalysis and a presentation of all of them is neither valuable nor feasible. Some of the early work does merit presentation, however, if only to provide a sense of perspective on the field. Wittig and coworkers demonstrated in 1947 the value of utilizing tetramethylammonium cations paired with trityl and fluorenide ions for alkylation in dry alcohol solution [1 ]. Jarrousse found that cyclohexanol and phenyl-acetonitrile could both be alkylated in a two phase system and the catalytic effect of quaternary ammonium salts was clearly recognized (see Eqs. 1.1 and 1.2) [2] Sarrett, in his classic cortisone synthesis, found that either Triton B or the Mannich base... 

As shown, both alkyl halides and Mannich base quaternary salts have been used as alkylating reagents. With j -nitrobenzaldehyde and ammonium acetate in acetic acid a Mannich reaction occurs, the intermediate (37) so produced reacting further to give a pyrimidine ... 

Ricci, Bernardi and coworkers demonstrated that asymmetric addition of aryl-sulfonylacetates to both N-Boc and N-Cbz imines can also be conducted very efficiently when using quinidine derivatives of type 53 and 54 as a catalyst [68]. These asymmetric Mannich-type reactions require toluene at -30 °C, aqueous K3PO4 as the base, and 10mol% of the quaternary ammonium salt for optimal... 

Nevertheless, in many cases, hydrogcnolysis docs not occur readily however, the ammonium salt of the Mannich base appears more suitable for a successful reaction. Thus, several ortho-phenolic Mannich bases arc hydrogenated as hydrochlorides, in order to avoid the presence of the intramolecular hydrogen bond between OH and N, which is responsible for the weak reactivity of the free Mannich base. ITie ferroccnyl Mannich base 282, containing both tertiary and quaternary amino groups, gives 2-di-methylaminomethyl-l-(2-methylferroccn-l-yl) ferrocene (283) upon reaction of the more reactive quaternary ammonium moiety. ... 

Aminomethylation of lactone enolates with the Eschenmoser salt followed by neutralization (workup) yields the corresponding Mannich bases. Their conversion to quaternary ammonium iodides followed by treatment with DBU (1,5-diazabicy-clo[5.4.0]undec-5-ene) leads to a-methylene lactones. 

The new chiral ammonium betaine 112 was developed and utilized by Ooi et al. as a bifunctional organic base catalyst for Mannich-type reaction of a-nitrocarbox-ylates [63]. This quaternary ammonium compound is an internal salt, unlike the aforementioned intermolecular ion-pairing ammonium salts. Consequently, the anion could act as a Brpnsted base and deprotonate a pronucleophile. The resulting... 

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