Mannich bases double

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 ... 

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. 

Double bond migration may occur when metal hydrides arc allowed to react with acetylenic iodomethylated Mannich bases, with the fomiation of allenc28S (Fig. Ill), instead of the expected methyl-acetylene derivative. - ... 

The prochirality of aldehydes other than formaldehyde is frequently exploited in order to obtain asymmetric Mannich bases 99A and B, as the reaction with substrate may occur from either side of the double bond plane of the aminomethylating agent (Fig. 38). 

Elimination of the amino group of the Mannich base followed by addition of the CH-active reagent to the double bond of the vinyl derivative (Michael-type addition) so formed... 

The present chapter deals with the application of Mannich aminomethylation or Mannich bases to the synthesis and modification of macromolecular compounds. As summarized in Fig. 150, a remarkable number of different combinations exist, as the Mannich reaction enables us (a) to perform polymerizations by using bifunctional substrate and amine as well as (d) to functionalize polymeric derivatives behaving, alternatively, as substrate or amine components of Mannich synthesis. On the other hand, the manifold reactivity of Mannich bases makes it possible (b) to produce polymers by amino group replacement with bifunctional nucleophiles or to polymerize suitable moieties (e.g., double bonds) present in the base. Furthermore (e), macromolecular compounds can be subjected to amino group replacement as well as to various other reactions given by Mannich bases. Finally (c), crosslinked derivatives are obtained from oligomeric or polymeric products through any of the above mentioned methods. 

In the hydrogenolysis of acetylenic Mannich bases, rearrangement with double bond migration, accompanying the elimination of the amine, may take place with formation of an alicne derivative instead of the expected methyl alkyne. 

To accomplish a quantitative treatment of the concentration-time plots it was first necessary to elucidate the reasons for the observed deviations after longer time intervals. A consecutive reaction of the a,jS-unsaturated ketones was expected. Because the cyclopentanone derivative 5, containing an exocyclic double bond, can undergo isomerization (Erskine and Waight, 1960) further attention was centred on phenyl vinyl ketone (7) formed in reaction (2b). In a separate study, reported on p. 25 it was found that phenyl vinyl ketone reacts imder the conditions used with hydroxide ions at a measurable rate at pH above about 9. Because the Mannich bases 4 and 6 have piT values of about 9-5 and 9-6, respectively, the rate of elimination was measurable with these compounds at pH > 8-5. Hence practically over the whole pH-range in which the elimination can be studied, the consecutive reaction of the phenyl vinyl ketone formed had to be taken into account. In preference to the development of a mathematical treatment for the system of consecutive reactions a more suitable Mannich base, for which such complications would be absent, was looked for. 

Hence, depending on the conditions, elimination reactions of Mannich bases follow irreversible or reversible kinetics. When the leaving amine is practically completely protonated as soon as it is formed, it cannot add to the double bond and the reaction becomes irreversible. Only when the pH-value is sufficiently high, so that the amines are present predominantly in the free base form, is the rate of addition comparable to that of elimination, and reversible kinetics are observed. 

To achieve more information that would allow a distinction between these possibilities the effects of substituents (including deuterium) on methylene groups of )3-morpholinopropiophenone and of ring-size of Mannich bases in which the double bond formed would be between ring carbons are currently being studied. 

A second challenge is the toxitity potential of some prodrugs, namely, a toxic metabolite formed from the promoiety or a reactive metabolic intermediate generated during the activation of some bioprecursors. The former case is illustrated by the liberation of formaldehyde, as seen with Mannich bases or some double esters [1,4]. The latter case involves a very few known examples of failed bioprecursors whose activation was via a reactive and toxic intermediate. Thus, arylacetylenes were examined as potential bioprecursors of nonsteroidal anti-inflammatory agents [1]. Although the nature of the final (and stable) metabolite (an arylacetic add) was known, researchers at the time were not aware that the metabolic pathway involved an intermediate and highly reactive ketene. 

Mannich bases, transamination with amidines, cyclic 18, 482 suppl. 21 Mannich reaction —, N-heterocyclics by — 21, 798 —, double, N-heterocycles by — 13, 775 suppl. 21 anfi-Markownikoff hydro-halogenation 14, 205 suppl. 21... 

Finally, the third method for synthesizing (478), developed by Johnson et al.[577,578], also starts from the Mannich base (496). Its condensation with cyanoacetic ester led to the cyanoke toes ter (493), which, by the Stobbe reaction with dimethyl succinate,formed compound (492). On hydrogenation of the double bond and angular methylation, this was converted into the cyanoester (489) which, in a similar manner to the preceding case, gave the intermediate (478) on treatment with methanolic hydrogen chloride. 

Pyrrole-based PNP and PNNP pincer diphosphines were synthesized starting from pyrrole and dipyrrolyl-diphenylmethane utilizing a double Mannich reaction and then the reaction of the Mannich bases with two equivalents of Ph2PH at 110-150 °C. It is noteworthy that there was no need to use Ph2PLi in the substitution reaction. The bisphosphines were converted to the oxides and sulfides (Scheme 10). ... 

Tropinone is a structural component of several alkaloids, including atropine. The synthesis is based on a double Mannich process with iminium ions as intermediates. The Mannich reaction in itself is a three-component domino process, which is one of the first domino reactions developed by humankind. 

In 2003, Williams and Mander reported a method designed to access the hetisine alkaloids (Scheme 1.3) [27]. This approach, based upon a previously disclosed strategy by Shimizu et al. [28], relied on arylation of a bridgehead carbon via a carbocation intermediate in the key step. Beginning with (1-keto ester 46, double Mannich reaction provided piperidine 47. Following a straightforward sequence, piperidine 47 was transformed to the pivotal bromide intermediate 48. In the key step, bromide 48 was treated with silver (I) 2,4,6-trinitrobenzenesulfonate in nitro-methane (optimized conditions) to provide 49 as the most advanced intermediate of the study, in 54 % yield. 

Systematic bond disconnection of porantherine [151] with recognition of the double bond-carbonyl equivalence for synthesis generated a synthetic pathway which is based on two intramolecular Mannich reactions. The symmetrical nature of the amino diketone precursor identified by the retrosynthetic analysis facilitates its preparation and subsequent transformations. Moreover, all the hetero atoms (donors) are separated by odd-numbered carbon chains and such arrangements are most amenable to normal modes of assembly. 

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