retro-Mannich Reaction Research Articles

The Mannich reaction in the synthesis of N,S-containing heterocycles

Reactions of 6-aryl-5-cyano-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidines with formaldehyde and primary amines gave earlier unknown 3,4-dihydro-2H,6H-pyrimido[2,1-b]-[1,3,5]thiadiazine derivatives in 58–94% yields. In boiling AcOH, these pyrimidothiadiazines underwent the retro-Mannich reaction leading to the starting pyrimidine-2-thiones. The structure of 3-(4-ethoxyphenyl)-6-oxo-8-phenyl-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3,5]thiadiazine-7-carbonitrile was studied by X-ray diffraction analysis.

(E)-3-(2-Alkyl-10H-phenothiazin-3-yl)-1-arylprop-2-en-1-ones: preparative, IR, NMR and DFT study on their substituent-dependent reactivity in hydrazinolysis and sonication-assisted oxidation with copper(ii)nitrate

A series of novel 3(5)-aryl/ferrocenyl-5(3)-phenothiazinylpyrazoles and pyrazolines were obtained by substituent-dependent regioselective condensation of the corresponding (E)-3-(2-alkyl-10H-phenothiazin-3-yl)-1-aryl/ferrocenylprop-2-en-1-one with hydrazine or methylhydrazine in acetic acid. The different propensity of the primary formed beta-hydrazino adducts to undergo competitive retro-Mannich reaction was interpreted in terms of tautomerisation equilibrium constants calculated by DFT using a solvent model. The regioselectivity of the cyclisation reactions with methylhydrazine and the substituent-dependent redox properties of pyrazolines were also rationalized by comparative DFT calculations performed for simplified model molecules. On the effect of ultrasound-promoted oxidation with copper(II)nitrate phenothiazine-containing pyrazolines, enones and oxo-compounds were selectively transformed into sulfoxides. Only one sulfoxide enone was partially converted into an oxirane derivative. The structure of the novel products was determined by IR and NMR spectroscopy including COSY, HSQC, HMBC and DNOE measurements.

Reaktionen vinyloger Hydrazide mit Carbiminium-Verbindungen / Reactions of Vinylogous Hydrazides with Carbiminium Compounds

Vinylogous hydrazides of type 1 react with methyleniminium salts only in 2-position to form aminomethylated compounds 2·HX. The oxidation of 1 with Hg(II)-EDTA results in a twofold dehydrogenation to the lactams 3, which may be aminomethylated in 2-position. The methylpiperidine derivatives 4 and 5 with Hg(II)-EDTA yield in a monodehydrogenation cyclic iminium compounds. These are isolated as 6 · ClO4 and 7 · ClO4 respectively, and show an enolimine structure, which is not accessible to intramolecular aminoalkylation. With the 2-methylsubstituted enhydrazinones 11 methyleniminium salts cause an attack at 4-position, vinylogous to the carbonyl function, and produce the aminomethylated derivatives 13. Oxidation of 11 gives rise to the lactams 12, which are inert to Mannich reagents. The Mannich bases 2 undergo an amine elimination to form the pyrazolinium betaines 15. The aminomethylated lactams 20 show, in addition to amine eliminations, retro Mannich reactions and from the cleavage products methylenebis(lactam-enhydrazinones) 21 result. Formaldehyde and primary amines generate with 1 and 3 the tetrahydropyrimidine derivatives 24/25 and 22/23, respectively. Hexahydroacridinediones 27 are obtained from the reaction of 21 with formaldehyde and acetic acid.

Heterocyclization of Oximes of 3,5‐Dimethyl(1,3,5‐trimethyl)‐2,6‐diphenylpiperid‐4‐ones and N‐Benzylpyrrolid‐3‐ones with Acetylene in a Superbasic Medium.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Acid‐Promoted Retro‐Mannich Reaction of N‐Protected Tropenones to 2‐Substituted Pyrroles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Heterocyclization of Oximes of 3,5-Dimethyl(1,3,5-trimethyl)-2,6-diphenylpiperid-4-ones and N-Benzylpyrrolid-3-ones with Acetylene in a Superbasic Medium

It has been established that on heterocyclization of 3,5-dimethyl-2,6-diphenylpiperid-4-one oxime with acetylene in a superbasic medium migration of the 3a-CH3 group to the anionic nitrogen atom occurs, leading to the formation of 5,7-dimethyl-4,6-diphenyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine. The formation of the N-anion causes aromatization of the tetrahydropyridine ring. Tetrahydropyrrolo[1,2-c]pyrimidines are formed in the Trofimov reaction as a result of decomposition of the intermediate 3H-pyrrole in a retro-Mannich reaction.

Retro‐Mannich Reactions of 3‐Alkyl‐3,4‐dihydro‐2H‐1,3‐benz[e]oxazines and the Synthesis of Axially Chiral Resorcinarenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The chemistry of zerumbone. Part 5: Structural transformation of the dimethylamine derivatives

Zerumbone ( 1 ) and its 6,7-epoxide ( 2 ) react with ammonia and dimethylamine regio- and stereospecifically, affording monoamines 3 , 4 , 7 and 8 . All adducts have the same relative configuration at C2 and C3. The conjugate amination is thermodynamically controlled to arrive at a single diastereomer. At 15°C 7 reacts with cyanide to give aminonitrile 10 as the single product, while at 30°C, acyclic aminonitrile 11 is also formed. The reaction with 8 affords at 0°C bicyclic aminonitrile 12 of the asteriscane skeleton, while at 30°C or higher temperature, mixtures of 12 and tricyclic nitriles 13 and 13′ are obtained. Refluxing of 7 , 8 and 10 in aqueous acetonitrile promotes scission of the zerumbone ring by retro-Mannich reaction to provide acyclic aldehydes 16– 18 , respectively. The dimethylamino group of 7 , 8 and 10 is eliminated stereospecifically by Cope- and base-catalyzed eliminations to regenerate the zerumbone skeleton in the products 1 , 2 and 21 . Cope elimination of 12 results in a mixture of 13 and 13′ by deaminative transannular etherification.

Retro-Mannich reactions of 3-alkyl-3,4-dihydro-2 H-1,3-benz[ e]oxazines and the synthesis of axially chiral resorcinarenes

Intermediates involved in the conversion of 3-alkyl-3,4-dihydro-2 H-1,3-benz[ e]oxazines into 2- N, N-dialkylaminomethylphenol derivatives, using morpholine and other high boiling secondary amines, have been identified and characterised. Additional experiments have established the involvement of o-quinone methide intermediates in the retro-Mannich reactions. Axially chiral resorcinarenes have been prepared by utilising the exchange reactions.

ChemInform Abstract: Highly E-Selective Synthesis of α,β-Unsaturated Amides from N-2-Methoxyphenyl Aldimines via Lithium Ynolates.

Abstract Lithium ynolates reacted with N- 2 - methoxyphenyl (OMP) aldimines to afford α,β-unsaturated amides in excellent E -selectivity via a retro-Mannich reaction of the 2:1 adducts (β-lactams), followed by cleavage of the β-lactam enolates.

Highly E-selective synthesis of α,β-unsaturated amides from N-2-methoxyphenyl aldimines via lithium ynolates

Lithium ynolates reacted with N-2 -methoxyphenyl (OMP) aldimines to afford α,β-unsaturated amides in excellent E-selectivity via a retro-Mannich reaction of the 2:1 adducts (β-lactams), followed by cleavage of the β-lactam enolates.

Dicompartmental Ligands with Hexa- and Tetradentate Coordination Sites: One-Step Synthesis of Ligands and Metal Complexes and Their X-ray Structure Analysis

Examples of interesting ligands previously requiring lengthy synthetic procedures have been prepared by one-step routes, opening the way to more extensive studies of their complexes and to possible applications. New dicompartmental ligands bearing picolyl pendant arms on the amine nitrogen donors have been synthesized, via the Mannich condensation, from 5-substituted salicylaldehydes, formaldehyde, and N,N‘-bis(2-pyridylmethyl)-1,2-diaminoethane. The protonated acyclic ligand salt, two mononuclear complexes of a macrocyclic ligand with a second compartment featuring a Schiff base, and one of the decomposition products resulting from a retro-Mannich reaction have been structurally characterized. The ligand salt (L1b) has an extended conformation with the ethylenediamine fragment displaying the trans configuration, very different from that of the corresponding closed-site macrocyclic complexes NiH2(L2b)2+ and ZnH2(L2b)2+. The mononuclear macrocyclic complex NiH2(L2b)2+ has a much smaller ligand twist than the corresponcing Zn(II) complex. The degree of ligand distortion is correlated with the M−N bond length between the metal ions and the pyridine nitrogens; longer M−N bonds cause the pyridine rings to tilt and twist the phenolic rings out of the main ligand plane. The ability of the macrocyclic ligand L2b to accommodate a second metal ion has been demonstrated by successful synthesis of dinuclear complexes. The free carbonyl groups of the open-site ligand were transformed into oxime groups, and the corresponding dinuclear bis(nickel) complex has been prepared. Acetal formation by the free carbonyl groups of ligand and retro-Mannich rearrangements are found to be possible pathways for the decomposition of this family of dicompartmental ligands.

6-Demethyl-6-halo- and 6-Demethyl-6-thiomitomycins: Synthesis of Novel Mitomycin Derivatives Involving a Tandem Michael Addition/Retro-Mannich Reaction Sequence

Synthesis of novel 6-demethyl-6-halomitomycins (3, 4, 6, and 7) and 6-demethyl;6-thiomitomycins (5 and 8) is described from key intermediates, namely, 6-demethyl-7,7-(ethylenedioxy)-6,6-dihalo-6,7-dihydromitosanes (18 and 19) and 6-demethyl-7,7-(ethylenedioxy)-6,7-dihydro-6-thiomitosane (20), respectively. Compounds 18-20 were prepared through a tandem Michael addition and a retro-Mannich reaction sequence (N-halosuccinimide or cationic arylsulfenyl species in the presence of Et 2 NH) on 10

First synthesis of mitomycins completely labeled at the C-6-methyl by 13CH3 and CD3

The C-6-methyl group of mitomycins was completely labeled with carbon-13 or deuterium for the first time. The synthesis was accomplished by the C-6-methylation of 6-demethyl-7,7-(ethylenedioxy)-6-(phenylseleno)mitosane 8 that was formed by a novel replacement of the methylene moiety of 6-demethyl-7,7-(ethylenedioxy)-6-methylenemitosane 10 by a phenylseleno group, and followed by conversion to the mitomycins. For the synthesis of 8, the authors found that selenamide 11 is an excellent reagent for the replacement. They have also determined that the replacement proceeded via the addition of 11 to the methylene of 10 with a subsequent retro-Mannich reaction. 15 refs.

Synthetic studies relevant to biosynthetic research on vitamin B12. Part 11. Modification of the east and west building blocks and study of different assembly methods for synthesis of isobacteriochlorins

The eastern and western building blocks required for the photochemical route to isobacteriochlorins have been synthesized by a C–C bond-forming step which leaves a cyano group on the bridge carbon, e.g.5. Two methods have been developed to remove this cyano residue which use retro-Mannich reactions to eliminate either an aminomethyl group, resulting from reduction of the nitrile, or the corresponding sulfonamido group. Two effective ways to carry out the final steps of the isobacteriochlorin synthesis have also been developed.

Triple (Grob) Fragmentation. Retro-Mannich Reactions of 1-Aza-adamantane Derivatives

The first triple (Grob) fragmentation is described. The process (mechanism) involves retro-Mannich reactions. Easily accessible 1-aza-adamantane derivatives 1 are converted to substituted 5-chloro-resorcinols 5.

Studies on histionicotoxin: rearrangement of the spirocyclic histrionicotoxin carbon skeleton into the fused pumiliotoxin skeleton

On treatment with acid the spirocyclic ketoamine 5 undergoes a retro-Mannich reaction followed by recondensation to give the unsaturated imine 8 , thus converting the histrionicotoxin carbon skeleton into the pumiliotoxin C skeleton.

ChemInform Abstract: NOVEL ISOMERIZATION AND RETRO‐MANNICH REACTION OF 1,1,2,2‐TETRAACYLCYCLOPROPANES

1,1,2,2-Tetraacylcyclopropanes (1a, 1b) were rearranged into nine-membered enol lactones (2a, 2b) by tertiary amines, while primary arylamines brought about retro-Mannich reaction to give bisdimedone (4) and Schiff base.

NOVEL ISOMERIZATION AND RETRO-MANNICH REACTION OF 1,1,2,2-TETRAACYLCYCLOPROPANES

Abstract 1,1,2,2-Tetraacylcyclopropanes (1a, 1b) were rearranged into nine-membered enol lactones (2a, 2b) by tertiary amines, while primary arylamines brought about retro-Mannich reaction to give bisdimedone (4) and Schiff base.

Isocarbostyrils. II. The Conversion of 2-Methyl-4-acyl-5-nitroisocarbostyrils to 2-Substituted Indole-4-carboxylic Acids

The sulfuric acid catalyzed acylation of 2-methyl-5-nitroisocarbostyril with carboxylic acid anhydrides gave the corresponding 4-acylated derivatives 3, which underwent reductive cyclization to 2-substituted derivatives of 4-methyl-1,3,4,5-tetrahydropyrrolo[4.3.2.de]isoquinolin-5-one (4). Alkaline hydrolysis of the six-membered lactam in 4 was accompanied by a retro-Mannich reaction to produce 2-substituted indole-4-carboxylic acids in about 40 % overall yield from 3.