Mannich condensations forming

Hydroxyisoquinolines. Hydroxy groups in the 5-, 6-, 7-, and 8-position show phenoHc reactions for example, the Bucherer reaction leads to the corresponding anainoisoquinolines. Other typical reactions include the Mannich condensation, azo-coupling reactions, and nitrosation. Both 0-methyl and /V-methyl derivatives are obtained from the methylation of 1-hydroxyisoquinoline, indicating that both tautomeric forms are present. Distillation of various hydroxy compounds, eg, 1- and 4-hydroxyisoquinoline, with zinc dust removes the oxygen. Treatment of 1-isoquinolinol with phosphoms tribromide yields 1-bromoisoquinoline [1532-71 -4] (178). 

The Mannich condensation has traditionally been carried out in the presence of water as a three-component condensation involving a carbonyl compound (or related carbon nucleophile), formaldehyde, and a primary or secondary amine. The initial step is a condensation between the latter two reactants to form a mono- or dialkyl(methylene)ammonium ion which subsequently serves as the electrophilic partner in the reaction. With unsymmetrical ketones aminomethylation generally occurs at both positions to give mixtures of isomeric 3-amino ketones. The ratio of the isomers depends strongly on the structure of the ketone, and the more highly branched (3-amino ketone usually predominates. 

Mannich condensations permit one-step reactions to form the following substances from substantially less complex starting materials. Identify a potential starting material that would give rise to the product shown in a single step under Mannich reaction conditions. 

Tyrosine may be targeted specifically for modification through its phenolate anion by acylation, through electrophilic reactions such as the addition of iodine or diazonium ions, and by Mannich condensation reactions. The electrophilic substitution reactions on tyrosine s ring all occur at the ortho position to the —OH group (Figure 1.11). Most of these reactions proceed effectively only when tyrosine s ring is ionized to the phenolate anion form. 

Primary nitramines react with amines in the presence of an aldehyde to form 1,3-amino-nitramines in a reaction analogous to the Mannich condensation. In these reactions the amine and aldehyde component combine to form an intermediate imine which is then attacked by the nitramine nucleophile. 

Dimethylolnitramine (252) readily participates in Mannich condensation reactions treatment of a aqueous solution of (252) with methylamine, ethylenediamine and Knudsen s base (254) (generated from fresh solutions of ammonia and formaldehyde) yields (253), (255) and (239) (DPT) respectively. The cyclic ether (258) is formed from the careful dehydration of dimethylolnitramine (252) under vacuum. ... 

Adolph and Cichra synthesized a number of polynitroperhydro-1,5-diazocines and compared their properties with the powerful military explosive HMX. A type of Mannich condensation was used to form the 1,5-diazocine rings the condensation of ammonia and methylamine with formaldehyde and bis(2,2-dinitroethyl)nitramine (46) forming diazocines (47) and (48) respectively. 1,3,3,7,7-Pentanitrooctahydro-1,5-diazocine (47) is A-nitrated to 1,3,3,5,7,7-hexanitrooctahydro-l,5-diazocine (52) in near quantitative yield using mixed acid. 

Compounds with a terminal triple bond can undergo a Mannich condensation with form aldehyde and secondary aliphatic or alicyclic amines [193). 

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... 

TOSMIC can be converted into an A-tosylmethylimidic ester or thioester (10) which will react with an aldimine to form a 1,2,5-trisubstituted imidazole (Scheme 4.2.3). These esters (10) can be made from A-tosylmethylacetamidc (from the Mannich condensation of p-toluenesulfonic acid, formaldehyde and acetamide [10]), which is smoothly converted by P4S10 in DME into the thioamide which forms the 5-methylated imidate when treated with methyl fluorosulfonate in dichloromethane. Yields of the Al-tosylmethylimidic thioesters are good (65-93%) they are fairly stable crystalline solids which are best stored under nitrogen at —20°C. In reaction with an aldimine in the presence of sodium hydride or potassium t-butoxide (in DME -DMSO or... 

The idea that the berberine bridge might be formed by the oxidative cyclization of an iV -methyl group rather than from a Mannich condensation of formaldehyde was conceived independently by both groups 124) and proved to be correct by separate experiments. 

Many cyclic amines are prepared by reduction of cyclic imines (see Section 1.20.3), or amides (see Section 1.20.4). Nitro-, amine- and carboxyl-substituted cyclic amines are formed by Mannich condensations (see Section 1.20.6). 

Mannich condensation of [Cu(en)2]2+ with methanal and di(m)ethyl-malonate forms [ 6,6,13,13-tetrakis(carbo(m)ethoxy)-cyclam copper(II)]2+ (97), in approximately 10% yield in methanol,92 approximately 20% in DMF,93 with lower yield for the reaction with Ni11 (Scheme 25). The ester functions are hydrolyzed in base to form the tetrakis(carboxyl)-substituted cation (98), which readily decarboxylates in acid to form the trans- 6,13-bis(carboxyl)-substituted cation (99).92 The carboxyl groups of (99) have been converted to carbomethoxyl, carbamoyl, (m)ethylcarbamoyl, and hydrazinocarbonyl functions.94... 

Spiro-biscyclam (133) has been prepared by reduction of the spiro-bis(dioxo-cyclam) (131),171 formed from the spiro-octaamine (130) by reaction with diethyl malonate (Scheme 31). A nitroethane/methanal Mannich condensation of the Cu11 compound of (130) formed the spiro-bis(nitro-methyl-cyclam) (132), which reduces to the spiro-bis(amino-methyl-cyclam) compound (134).175... 

Hohenlohe-Oehringetf used the carboethoxymethyl reagent for a Mannich condensation with methylamine and phenylacetaldehyde to form the 4-piperidone (5) in moderate yield. 

Control of the pH is also of importance for the Mannich-based bispidine synthesis. Formation of an aldol product competes with the Mannich condensation in the basic pH region. It is for this reason that, in some cases, the reaction is sensitive to the order in which the reactants are added to the reaction mixture. It is possible to add the aldehyde and amine components one after another to a solution of the CH-acidic compound, but sometimes the aldol reaction can be disfavored by changing the order. This allows the imminium ion to be formed in advance. The precursors of 45 and 46 have been prepared by this method. In some cases, it has been useful to use a protonated amine component as the acetate salt (e.g., 49 or precursors for 44, 47, and 48), as the chloride salt (e.g., 11) or to carry out the reaction in acetic acid. Aromatic amines (e.g., aniline) give rise to para-substituted aromatic amines if the solution is not approximately neutral. In a very elegant procedure, a condensate of formaldehyde and aniline, which is the trimeric methyleneaniline, was prepared separately, and treated in the Mannich reaction with dimethyl acetonedicarboxylate and formaldehyde to yield the 3,7-diphenylbispidone... 

Mannich condensation takes place when piperidine hydrochloride, acetophenone, paraformaldehyde and HCl are refluxed for several hours to yield 3-piperidino propiophenone, which upon grignardization with cyclopentyl magnesium bromide followed by neutralization of the cycrimine base forms the official compound. 

The family Papaveraceae Juss. is subdivided into the subfamilies Hypecoideae Prantl and Kiindig and Papaveroideae A. Br. It embraces 23 genera and 430 species. The Fumariaceae DC. include 7 genera with 350 species. In the literature, the alkaloids of about 168 species of the Papaveraceae and 90 species of the Fumariaceae have been described. A characteristic feature of these two families is (with a few exceptions, e.g.. Section IV) the presence of alkaloids derived from tetrahydroisoquinolines. These alkaloids arise from phenylalanine by condensation of dopamine with 3,4-dihydroxyphenylacetaldehyde and subsequent Mannich condensation to yield norlaudanosoline as the primary condensation product (Fig. 2). Other intermediates formed during the biosynthesis of more complicated constitutional types of isoquinoline alkaloids are (/ )-(-)- or... 

In the Mannich condensation, a C-C-N system is generated by the addition of a carbanion to the Schiff base formed by condensation of a ketone or aldehyde with an amine. Both primary and secondary amines may participate (Fig. 27.2b). Charged intermediates produced by the involvement of secondary amines facilitate the reaction by increasing the electron deficiency at the carbon atom which is subject to attack by the carbanion species. As Mannich condensations occur best at about pH 6-7, appreciable amounts of the protonated Schiff base and the attacking anionic species can exist (Geissman and Crout, 1969). 

The approximately 80 known pyrrolidine alkaloids possess a 5-membered nitrogen-containing ring (Massiot and Delaude, 1986 Binder, 1993). Several subgroups of pyrrolidine alkaloids arise by condensation of these units with other molecules, Pyrrolidine bases usually are modified by additional Schiff-base formation, Mannich condensation, and aldol-type processes to yield other alkaloids of tiiis general class. For example, condensation of pyrrolidine derivatives with nicotinic acid is involved in the formation of pyridine alkaloids such as nicotine see Chapter 28). Pyrrolidine units react with acetyl- or malonyl-CoA and condense via a Mannich condensation to form compounds such as hygrine and cuscohygrine and tropane alkaloids see below). 

Both the biosynthesis and chemical synthesis are based on a Mannich condensation of a -phenylethyl-amine derivative with a carbonyl component (Fig.). Depending on the latter, the substituent at Cl can be H-, CH3- or an isoprenoid residue. Several molecules of A. a. can be linked to form oligomers by phenol oxidation, as in pilocereine. As secondary alkaloids, cacti also produce derivatives of p-phenylethylamine, e. g. hordenine and mescaline. 

A domino process of enamine 136 formation, N-allylation, aza-Claisen rearrangement and a final Mannich condensation was introduced by Florent [22g]. Aldehyde 135 was subsequently treated with pyrrolidine and allyl iodide 137 to give an E/Z mixture of the ammonium salts 138. Heating to 80 °C induced the Claisen rearrangement. The newly formed iminium ions 139 underwent intramolecular Mannich cycUzations. The final amine eUmination delivered the spiro ketones 140 with 38% yield as a 2 1 mixture of diastereomers. The formed material should serve as a key compound in diverse cyclopentenone prostaglandine total syntheses (Scheme 10.30). 

The Robinson annulation is the reaction of alkali metal derivatives of cyclohexanones with a-,p>unsaturated methyl ketones to produce cycloketones and polycycloketones. The standard method for Robinson annulation is exemplified in the mechanism shown above. For the synthesis of the 1,5-diketone side chain, the enolate nucleophile reacts with a Michael acceptor this Michael acceptor is usually a substituted vinyl ketone or the parent methyl vinyl ketone (MVK), although the latter gives low yield due to its propensity to polymerize under the standard reaction conditions. To overcome the drawbacks for using MVK, Robinson, McQuillin and Du Feu introduced the Robinson-Mannich variation of the annulation reaction. This modification uses a quatemized Mannich base formed from the vinyl entity the Maimich base is made in situ and acts as a methyl vinyl ketone precursor after it is converted to its methiodides. The formed methiodides of the Mannich adduct 4-(trimethylamino-2-butanone) is condensed with sodioderivatives of ketones or with the parent ketone in the presence of sodium ethoxide. 

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