Mannich alkylation

Madclung synthesis, 27-30 Mannich alkylation, 106, 119 7-mcthoxyindole, procedure for, 8 6-methoxyindole-3-carboxaldehyde, procedure for, 115 116 methyl 4-[5-(benzyloxycarbonyl)indol-3-yl]methyl-3-methoxy-benzoate, procedure for, 108... 

Naphthyridin-3(57/)-one (29) underwent Mannich alkylation to give 4-dimethylaminomethyl-l,5-naphthyridin-3(5/7)-one (30) (Me2NH, CH20, EtOH, H20, 25°C, 4 h 73% analogs likewise).932... 

Bromo-8-(p-hydroxyanilino)-1,5-naphthyridine underwent extranuclear Mannich alkylation to give 3-bromo-8-[4-hydroxy-3,5-bis(4-methylpiperazin-l-yl)ani-lino]- 1,5-naphthyridine (31) (substrate, CH20, 1-methylpiperazine, EtOH, reflux, 30 h 50%) analogs likewise.1379... 

Pyrazinecarboxamide underwent Mannich alkylation to afford AKdibcnzy-... 

SCHEME 2.45 Chiral thiourea-catalyzed Mannich-alkylation cascade reaction. 

The third family (c. in Figure 9.1) less widespread, derived from the alkylphenols, offers as with the succinimides several possibilities of modification to the ratio of hydrophilic and lipophilic groups. Mannich s reaction of the alkyl-phenols also provides additives for lubricating oils. 

Synthesis Though we could follow the stepwise pattern of the disconnections, it is easier to add an activating group to the acetone molecule so that our starting materials are two molecules of acetoaeetate and formaldehyde. It turns out that Hagemann s ester can be made in two steps without having to alkylate the Mannich base ... 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

Under appropriate conditions 2-amino-4-alkylthiazoles are alkylated in the 5-position 2-acetylamino-4-methylthiazole reacts with dimethyl-amine and formaldehyde to afford the corresponding Mannich base (113) (372). 2-Amino-4-methyl-thiazole is alkylated in the 5-position by heat-... 

Mannich polyacrylamides can react with alkylating agents such as methyl chloride [74-87-3], CH Cl, methyl bromide [74-83-9], CH Br, and dimethyl... 

Conversion of the C-2 amide to a biologically inactive nitrile, which can be further taken via a Ritter reaction (29) to the corresponding alkylated amide, has been accomphshed. When the 6-hydroxyl derivatives are used, dehydration occurs at this step to give the anhydro amide. Substituting an A/-hydroxymethylimide for isobutylene in the Ritter reaction yields the acylaminomethyl derivative (30). Hydrolysis affords an aminomethyl compound. Numerous examples (31—35) have been reported of the conversion of a C-2 amide to active Mannich adducts which are extremely labile and easily undergo hydrolysis to the parent tetracycline. This reverse reaction probably accounts for the antibacterial activity of these tetracyclines. 

Although connection of polyalkylene or poly(alkylene oxide) groups to the polyamine is most commonly by the succinimide linkage, a different linking group is employed in another important class of ashless dispersants— the Mannich bases. They are prepared on a commercial scale by reaction of an alkylphenol with formaldehyde and a polyamine (173—177). The alkyl and polyamine moieties are similar to those used in the succinimide products. 

Benzimidazoline, 2,2-bis(trifluoromethyl)-synthesis, 5, 471 Benzimidazolines acidity, 5, 425 Benzimidazolinethiones Mannich reaction, 5, 390 synthesis, 5, 460 Benzimidazoline-2-thiones alkylation, 5, 444—445 S-alkylation, 5, 444 mercuration, 5, 445 reactions... 

Benzimidazolinone, 1,3-dimethyl-Friedel-Crafts reaction, 5, 429 Benzimidazolinone, 1,3-divinyl-synthesis, 5, 393 Benzimidazolinone, 6-methyl-Friedel-Crafts reaction, 5, 429 Benzimidazolin-2-one polymers, 1, 281 Benzimidazolinones alkylation, 5, 390 Friedel-Crafts reaction, 5, 429 Mannich reaction, 5, 390 nitration, 5, 429 reactions, 5, 442... 

Coumarin, 6-ethoxycarbonyl-4,5,7-trihydroxy-synthesis, 3, 805-806 Coumarin, 3-hydroxy-Mannich reaction, 3, 680 mass spectra, 3, 609 Coumarin, 4-hydroxy-alkylation, 3, 692 azo dyes from, I, 331 electrophilic substitution, 2, 30 IR spectra, 3, 596 Mannich reaction, 3, 680 mass spectra, 2, 23 3, 609 molecular structure, 3, 622 reactions... 

A -l,3,4-Oxadiazoline-5-thione, 2-phenyl-alkylation, 6, 440 Oxadiazolinethiones acylation, 6, 432 Mannich reaction, 6, 431 pK 6, 435 ring cleavage, 6, 433 Oxadiazoline-5-thiones acidity, 6, 435 stability, 6, 431 A -Oxadiazoline-5-thiones biological activity, 6, 445 synthesis, 6, 441 A -1,3,4-Oxadiazoline-5-thiones... 

Purines, N-alkyl-N-phenyl-synthesis, 5, 576 Purines, alkylthio-hydrolysis, 5, 560 Mannich reaction, 5, 536 Michael addition reactions, 5, 536 Purines, S-alkylthio-hydrolysis, 5, 560 Purines, amino-alkylation, 5, 530, 551 IR spectra, 5, 518 reactions, 5, 551-553 with diazonium ions, 5, 538 reduction, 5, 541 UV spectra, 5, 517 Purines, N-amino-synthesis, 5, 595 Purines, aminohydroxy-hydrogenation, 5, 555 reactions, 5, 555 Purines, aminooxo-reactions, 5, 557 thiation, 5, 557 Purines, bromo-synthesis, 5, 557 Purines, chloro-synthesis, 5, 573 Purines, cyano-reactions, 5, 550 Purines, dialkoxy-rearrangement, 5, 558 Purines, diazoreactions, 5, 96 Purines, dioxo-alkylation, 5, 532 Purines, N-glycosyl-, 5, 536 Purines, halo-N-alkylation, 5, 529 hydrogenolysis, 5, 562 reactions, 5, 561-562, 564 with alkoxides, 5, 563 synthesis, 5, 556 Purines, hydrazino-reactions, 5, 553 Purines, hydroxyamino-reactions, 5, 556 Purines, 8-lithiotrimethylsilyl-nucleosides alkylation, 5, 537 Purines, N-methyl-magnetic circular dichroism, 5, 523 Purines, methylthio-bromination, 5, 559 Purines, nitro-reactions, 5, 550, 551 Purines, oxo-alkylation, 5, 532 amination, 5, 557 dipole moments, 5, 522 H NMR, 5, 512 pJfa, 5, 524 reactions, 5, 556-557 with diazonium ions, 5, 538 reduction, 5, 541 thiation, 5, 557 Purines, oxohydro-IR spectra, 5, 518 Purines, selenoxo-synthesis, 5, 597 Purines, thio-acylation, 5, 559 alkylation, 5, 559 Purines, thioxo-acetylation, 5, 559... 

The side-chain cyanoethylation of alkyl thienyl ketones with acrylonitrile has been studied " and used for the preparation of 8-oxonitriles and S-oxoacids. Aminomethylation (Mannich reaction) of 2-acetylthiophene followed by steam distillation yielded 50% of 2-thienyl vinyl ketone, and has also been used for the synthesis of compounds of biological interest. ... 

Furthermore, a substitution of the amino group is possible. An important application of Mannich bases 4 is their use as alkylating agents ... 

Inclusion of the carbon atoms of an aromatic ring in the side chain sequence is apparently quite consistent with antlmalarial activity. Thus, reaction of p-acetamidophenol with formaldehyde and diethylamine affords the Mannich product, 79. This is then converted to the diamine (80) by saponification. Alkylation with the chloroquinoline, 70, affords amidoquine (81). The same sequence starting with the Mannich product in which pyrrolidine has been used as the amine (82) gives amopyroquine (83). 

Thus, reduction of the Mannich reaction product (65) from acetophenone leads to alcohol 66. Replacement of the hydroxyl group by chlorine (67) followed by displacement of halogen with the anion from o-cresol affords the ether 68. Removal of one of the methyl groups on nitrogen by means of the von Braun reaction or its modem equivalent (reaction with alkyl chloroformate followed by saponification) leads to racemic 69 which is then resolved with L-(+)-mandelic acid to give the levorotary antidepressant tomoxetine (69) [16]. 

Taking into account the close relationship to pyridines one would expect 2-pyridones to express similar type of reactivities, but in fact they are quite different. 2-Pyridones are much less basic than pyridines (pKa 0.8 and 5.2, respectively) and have more in common with electron-rich aromatics. They undergo halogenations (a. Scheme 10) [67] and other electrophilic reactions like Vilsmeier formylation (b. Scheme 10) [68,69] and Mannich reactions quite easily [70,71], with the 3 and 5 positions being favored. N-unsubstituted 2-pyridones are acidic and can be deprotonated (pJCa 11) and alkylated at nitrogen as well as oxygen, depending on the electrophile and the reaction conditions [24-26], and they have also been shown to react in Mitsonobu reactions (c. Scheme 10) [27]. 

In this reaction, methyl groups are cleaved in preference to other saturated alkyl groups. A similar reaction takes place between a Mannich base (see 16-15) and a secondary amine, where the mechanism is elimination-addition (see p. 430). See also 19-5. 

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