Mannich bases hydrogen compounds

Mannich Reaction The reaction of a compound with a reactive hydrogen with aldehydes (non-enol forming) and ammonia or a primary or secondciry amine to form a Mannich base (ciminomethylated compound). 

If the active hydrogen compound has two or three active hydrogens, the Mannich base may condense with one or two additional molecules of aldehyde and ammonia or amine, for example. 

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 ... 

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 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. 

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). 

Enones like this, with two hydrogen atoms at the end of the double bond, are called exo-methylene compounds they are very reactive, and cannot easily be made or stored. They certainly cannot be made by aldol reactions with formaldehyde alone as we have seen. The solution is to make the Mannich base, store that, and then to alkylate and eliminate only when the enone is needed. We shall see how useful this is in the Michael reaction in Chapter 29. 

Hydrogenation and organometal addition to the carbonyl group of Mannich bases of camphor and related compounds are also widely reported (see references in Chap. II,... 

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. 

C-Mannich bases deriving from hydrogen cyanide make it possible to obtain, upon hydrolysis of the cyano group, a-amino acids 516, which are employed largely as complexants the well-known ethylenediaminetetraacetic acid (EDTA) is the main representative of this group of compounds. 

Although formaldehyde has been most common, other aldehydes have also been used successfully for the formation of iminium ion. The Mannich reaction also proceeds with the other activated hydrogen compounds such as indole, furan, pyrrole and phenols. When primary amine is used, the Mannich base formed is a secondary amine and may undergo further condensation to yield tertiary amine. The Mannich base may eliminate an amine... 

Mannich bases formed by dialkylaminomethylation of various compounds containing an active hydrogen atom are useful intermediates in the synthesis of certain olefinic compounds. The tertiary amine group of the Mannich base is eliminated upon steam distillation or low-temperature pyrolysis (120°) of the hydrochloride. The over-all reaction is illustrated by the following preparation of an a., -olefinic ketone, ... 

Coyle and Bryant have reported the efficient synthesis of a triazabicyclo[3.3.0]octane system by the photocyclization of hydantoin derivatives. Thus irradiation of (295), synthesized by standard Mannich procedures, afforded the bicyclooctanes (296) in moderate to good yields. The process, akin to Norrish Type II behaviour, is a 1,6-hydrogen transfer followed by bonding in the resultant biradical (297). The bis-Mannich base compound (298) also photocyclizes, yielding (299). Coyle and his co-workers have also successfully applied the known reactivity of phthalimides to yield polycyclic compounds. Thus irradiation of (300) affords the cyclized compound (301). This can be converted into the protoberberine alkaloid skeleton (302) by treatment with aqueous HCl. The crown ether analogues (303) and (304) have... 

In these compounds, a strong, thermodynamically stable intramolecular hydrogen bond is formed between a phenolic OH group and an A,A-dialkylaminomethyl substituent in the 2-position (73). orf/jo-Mannich bases are excellent models for the investigation of... 

Two Schiff bases (A,iV -bis(5-bromosalicylidene)-1,2-diamino-ethane and 7-[( 1 -(5-bromo-2-hydroxyphenyl)methylidene)amino]-4-methyl-coumarin), and two appropriate Schiff-Mannich bases (A,JV-bis(5-bromo-3-[(diethylamino)methyl]salicylidene)-1,2-diaminoethane and 7-[( 1 -(5-bromo-3-[(diethylamino)methyl]-2-hydroxyphenyl)methylidene)amino]-4-methylcoumarin) capable of intramolecular hydrogen bonding have been investigated by multi-nuclear NMR methods in both solid and liquid phases. In all of the compounds under investigation tautomeric equilibrium involving an intramolecular hydrogen bond has been found. In the solid state the tautomeric... 

Bisaminomethylation, occurring when the active methylene compound contains more than one acidic hydrogen, is another possible side reaction. Reported cases of bisaminomethylation are rather infrequent, however, suggesting that the protonated P-ammonium group slows down the rate of enolization of the Mannich base relative to the unreacted active methylene compound. Thermodynamic factors reflected in the steric congestion of the bisaminomethylated product may also be important. 

Mannich bases are often valuable intermediates for preparation of unsaturated compounds. They are obtained by the action of formaldehyde and ammonia or a primary or secondary amine on compounds containing active hydrogen.77,78 When a Mannich base or its salt is heated, the amino group is split off and the unsaturated compound is formed. Unsaturated ketones,79 aldehydes,80 acids,77 and nitro compounds81 can all be thus prepared. 

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