Mannich base, formation

The reactivity of the 5-acyl group of 2-acylamino-5-acylthiazole in the formation of Mannich bases is greater than that observed for 2-amino-5-acylthia2ole (476). 

The resihency and dyeabihty of poly(vinyl alcohol) fibers is improved by a process incorporating -hydroxybenzaldehyde to provide a site for the formation of a stable Mannich base. Hydroxyl groups on the fiber are converted to acetal groups by -hydroxybenzaldehyde. Subsequent reaction with formaldehyde and ammonia or an alkylamine is rapid and forms a stable Mannich base that is attached to the polymer backbone (94). 

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). 

Chloral forms well-crystallized adducts (126) with diaziridines containing at least one NH group (B-67MI50800). Carbonyl addition products to formaldehyde or cyclohexanone were also described. Mixtures of aldehydes and ammonia react with unsubstituted diaziridines with formation of a triazolidine ring (128). Fused diaziridines like (128) are always obtained in ring synthesis of diaziridines (127) from aldehyde, ammonia and chloramine. The existence of three stereoisomers of compounds (128) was demonstrated (76JOC3221). Diaziridines form Mannich bases with morpholine and formaldehyde (64JMC626), e.g. (129). 

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. 

Because of their manifold reactivity, Mannich bases 4 are useful intermediates in organic synthesis. For example the elimination of amine leads to formation of an o ,/3-unsaturated carbonyl compound 8 ... 

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. 

The only instance of simultaneous substitution at C3 and C6 of the nucleus of kojic acid is in the formation of the Mannich bases (LXXVI) reported by Woods.102 However, discrepancies in the reported yields render the validity of structure LXXVI dubious. 

The toxic potential of metabolic intermediates, of the carrier moiety, or of a fragment thereof, should never be neglected. For example, some problems may be associated with formaldehyde-releasing prodrugs such as N- and 0-[(acyloxy)methy 1] derivatives or Mannich bases. Similarly, arylacetylenes assayed as potential bioprecursors of anti-inflammatory arylacetic acids proved many years ago to be highly toxic due to the formation of an intermediate ketene. 

The key step of the synthesis, which involved a classical Mannich condensation in the synthesis by Evans and Scott (as well as in the biogenesis of alkaloids in general [10]), is substituted by a 1,3-dipolar cycloaddition of a nitrone to a carbon-carbon double bond [11] which provides an alternative route for the formation of a new C(l)-C(2) bond with the concomitant creation of a 1,3-consonant relationship between an oxygen atom and a dialkylamino group. In order to arrive at a typical Mannich base two more steps are, however, necessary. The similarity between the two processes is shown is Scheme 13.2.7 ... 

Some 1,3-dinitroalkanes (145) have been synthesized from the reaction of nitroalkanes with a-nitroalkenes (144) generated in situ from the decomposition of Mannich bases (143) derived from primary nitroalkanes. Reported yields for these reactions are low and the formation of by-products limits the feasibility of the method. 

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. 

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]. 

In one route, tidopidine (1) was assembled via Sn2 displacement of 2-chlorobenzyl chloride (9) with 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (8). " The nucleophile 8 was synthesized by heating 2-thiophen-2-yl-ethylamine (6) with 1,3-dioxolane in the presence of concentrated hydrochloric acid. 1,3-Dioxolone gave better yields than with formaldehyde, paraformaldehyde and 1,3,5-ttioxane. The interesting transformation 6 —> 8 first involved the formation of the corresponding Mannich base 7, which then underwent a Pictet-Spengler type reaction to afford the ring-closure product 8. It was of interest to note that a possible intramolecular aminomethylation did not take place. 

A similar method involves the reaction of difluorocarbene on enones462 or on Mannich bases (205) with formation of furosteroids (206).463... 

The formation of the chromanochromans (286) during the reaction of the phenolic Mannich bases and 2-chloroprop-2-enonitrile probably arises through the decomposition of the base to a quinone methide and dimethylamine (80JOC3726). The initial product, a substituted 4//-chromene (285), undergoes a further [4+2]-cycloaddition to give the final product (Scheme 77). 

A new synthesis leading to a previously unknown 8-substituted indolizine involves initially the formation of the dihydropyridopyranyl ether (81) by reaction between a vinyl ether and a Mannich base obtained from 3-hydroxypyridine treatment with dilute hydrochloric acid... 

Conversion of a Mannich base hydrochloride into an a,/ -unsaturated carbonyl compound, is illustrated by the formation of phenyl vinyl ketone, which is obtained directly by steam distillation (Expt 6.147). Alternatively the Mannich base may be treated with methyl iodide to form the quaternary salt, which then gives the a,/ -unsaturated carbonyl compound by a base-catalysed elimination reaction. 

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