Cyclization Mannich reaction

In a modified approach, the carbolinyl acetate 393 underwent a Mannich reaction with formaldehyde and acetone to give the keto ester 396 which, with base, cyclized to the diketone 397. This diketone (397) has recently been used to prepare a number of interesting pentacyclic compounds. 

The aza-Cope/Mannich reaction takes advantage of the facility with which a y,<5-unsaturated itninium ion, such as 6, participates in a [3,3] sigmatropic rearrangement to give an isomeric species which is suitably functionalized for an intramolecular and irreversible Mannich cyclization (see intermediate 7). The aza-Cope rearrangement substrate 6 is simply an unsaturated iminium ion which can be fashioned in a number of ways from a homoallylic... 

Other cyclizations at phosphorus have been observed when certain phosphinates were used in the acid-catalyzed Mannich reaction. As observed previously with various phosphonous acid derivatives, reaction of aliphatic phosphinic acids with primary amines favored the formation of 2 1 adducts (73). Thus, glycine and other a-amino acids reacted under the typical conditions with excess formaldehyde and alkyl phosphonous acids to give the bis-phosphinylmethyl adducts 125. 

Morken et al. demonstrated that the combination of [Ir(COD)Cl]2 (2.5 mol %) and P(OPh)3 catalyzed the Mannich reaction of aldimine 164 and trifluorophenyl acrylate 165 at 60 °C. Under these conditions, the initially formed Mannich product undergoes cyclization to furnish the corresponding lactam 166 in 80% with high frans-seleclivily > 20 1 (Scheme 42) [73],... 

As predicted, l,2,3,4-13C-labeled acetone dicarboxylate (15) provided an intact three-carbon chain into lycopodine. It also helped to explain why two molecules of pelletierine (12) were not incorporated (Scheme 6.3) [12]. As before, lysine (6) is converted to piperideine (8) via a decarboxylation. Then a Mannich reaction of labeled 15 with 8 provides pelletierine 12. The other half of the molecule to be incorporated must be pelletierine-like (12-CC>2Na), still containing one of the carboxylates. An aldol reaction of the two pelletierine fragments and a series of transformations leads to phlegmarine 9. Oxidation of 9 involving imine formation between N-C5, isomerization to the enamine and then cyclization onto an imine (at N-C13), provides lycopodine 10. Phlegmarine 9 and lycopodine 10 are proposed as... 

The mechanism of imine formation is standard, as seen in the other examples. The cyclization reaction is then like the Mannich reaction, attack of an enol on to the iminium cation. This time though, the nucleophile is provided by the resonance effect from the phenol system. 

Sequential Mannich reaction of ester 210a or nitrile 210b, alkylation and displacement of quaternary ammonium salt affords azides 211. Further hydrogenation can be followed by intramolecular cyclization under basic conditions into pyrrolo-benzodiazepinone 212 (Scheme 44 (1994JHC1317, 1994S164)). 

Regioselective aminomethylation and subsequent cyclization of methyl 2,4-dihydroxybenzoate 517 was accomplished through a Mannich reaction with formaldehyde and primary amines in methanol to yield 3-substituted-3,4-dihydro-2/7-l,3-benzoxazine derivatives 518 (Equation 60). Simultaneous mixing of the reactants resulted in poor yields, but good yields were achieved by the pretreatment of paraformaldehye with a primary amine to form a Schiff base, followed by the addition of compound 517 <2001TL7273>. 

A model compound 15 containing an indole (3-lactam moiety in chartellines was synthesized from the Mannich reaction of isatin imine with ketene silyl acetal, followed by (3-lactam formation through cyclization of the resulting (3-amino acid 14 (Scheme 5) [52]. L-Proline-catalyzed direct asymmetric Mannich reactions of... 

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