Mannich reaction retro

Finally, in the last step, the chelating auxiliary had to be removed Ideally, one would like to convert 4.54 into ketone 4.55 via a retro Mannich reaction. Unfortunately, repeated attempts to accomplish this failed. These attempts included refluxing in aqueous ethanol under acidic and basic conditions and refluxing in a 1 1 acetone - water mixture in the presence of excess paraformaldehyde under acidic conditions, in order to trap any liberated diamine. Tliese procedures were repeated under neutral conditions in the presence of copper(II)nitrate, but without success. 

Apparently, 4.54 is extremely reluctant to undergo a retro Mannicli reaction. Riviere demonstrated that this behaviour is not unusual for (3-amino ketones. From the study of a large number of Mannich adducts. Riviere concludes that the retro Mannich reaction requires an aromatic group next to the carbonyl functionality. Qearly, 4.54 lacks this arrangement. 

Hydroxyprotoberberine 59a and ( )-corytencine (98) led to 13-acetoxy compounds 104,105, and 107 moreover, the 2,3,9,10,12-pentaoxy-genated protoberberine 108 was also obtained from 98 via the p-quinol acetate 106 through a retro-Mannich reaction followed by recyclization (74,75). Oxidation in dichloromethane instead of acetic acid proceeded differently, namely, 97 and 98 led to pentaoxygenated protoberberines 103 and 109 by introduction of an acetoxyl group at C-4 and C-12, respectively, via o-quinol acetates (76). 

More recently in 2001, Winkler and Kwak reported methodology designed to access the pyrrolidine core of the hetisine alkaloids via a photochemical [2+2], retro-Mannich, Mannich sequence (Scheme 1.3) [26]. In a representative example of the methodology, vinylogous amide 42 was photo-irradiated to give the [2+2] cycloaddition product 43. Heating cyclobutane 43 in ethanol provided enamine 44 via a retro-Mannich reaction. Exposure of enamine 44 to acidic conditions then effected a Mannich reaction, resulting in pyrrolidine 45. 

A novel intramolecular photocycloaddition involving vinylogous amides and allenes led to an interesting type lb entry to functionalized pyrroles <060L4031>. For example, photolysis of allene 11 provided fused pyrrole 12 via a [2+2] cycloaddition and retro-Mannich reaction. 

The above assumption has been supported by in vitro transformation of 4,21-didehydrogeissoschizine (32) to 5,6-dihydroflavopereirine (3) (108). Treatment of 32 with base supplied dienamine 149, which loses the (3-aldehydo ester unit attached to C-15 in a retro-Mannich reaction. Finally, two subsequent [1,5]-sigmatropic hydrogen migrations led to 5,6-dihydroflavopereirine (3), isolated as the perchlorate salt. 

Compounds in which two donor atoms are linked by a three-carbon chain undergo C-C bond cleavage readily. Well-known reactions are the retro-aldolization, retro Claisen, retro-Michael, and retro-Mannich reactions. Significant application of such processes to synthesis of complex natural products include approaches to caryophyllene [80], nootkatone [81], trihydroxydecipiadiene [82], hybridalactone [83], and mesembrine [84],... 

Here again, loss of Y = H would result in rearomatization and formation of 12, but in the case of Y = Me, this cannot occur. However, assistance by the amine nitrogen lone pair can aid the rearomatization process, producing the copper-bound phenol product and an imininm salt. Hydrolysis during the workup procedure could release the 2-meth-ylphenol product and result in a retro-Mannich reaction to give the observed secondary amine (PY2) and formaldehyde. A small amount (<10%) of N—Me—PY2 is often observed as a byproduct and its yield is at the expense of the PY2 and formaldehyde thus, it appears to be derived from direct reduction of the intermediate iminium salt [167],... 

Scheme3.3. Retro-Diels-Alder [9], retro-aldol [10] and retro-Mannich reaction [11] of strained substrates.

Under certain circumstances, the conjugate addition and cycloaddition reaction pathways overlap for a,P-unsaturated electrophiles. For example, when the 2,5-dimethylpyrrole complex 22 is combined with 1 equiv of MVK in acetonitrile, a 1 1 ratio of the p-alkylated 3//-pyrrole complex 96 and the a-alkylated 2Z/-pyrrole complex 98 is isolated (Figure 18). When the reaction is monitored by H NMR in CD3CN, an intermediate 7-azabicyclo[2.2.1]heptene complex (97) is observed at early reaction times, and eventually converts (tm 1 h) to compound 98 via a retro-Mannich reaction followed by proton transfer. 

With Q = N, a similar fragmentation reaction is possible (retro-Mannich reaction), which leads to an imine or an iminium ion [57]. Fragmentations of this type have been frequently used for substrates of type A3 but can also be found for substrate class A2, A5, and A6 (vide infra). 

Spiropiperidine Alkaloids.—The spirocyclic keto-base (18), which possesses a histrionicotoxin skeleton, undergoes an acid-catalysed retro-Mannich reaction, followed by re-condensation, to afford the unsaturated imine (19), with a pumiliotoxin skeleton. A mechanism for the transformation has been proposed.29... 

As mentioned at the beginning of this chapter the retro aidol and the retro Mannich reaction can be used for ring expansion of proper substituted bicyclic systems. 

Scheme VIII/24. Examples of retro Mannich reaction in ring enlargement, a) NaOC2H5, C2H5OH.

In the reaction of 3,5-dimethyl-2,6-diphenylpiperid-4-one oxime (10) with acetylene and RbOH-DMSO, migration of the 3a-Me group to the anionic nitrogen atom occurred, leading to 5,7-dimethyl-4,6-diphenyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine (11) (04CHE326). The formation of the N-anion caused aromatization of the tetrahydropyridine ring. Tetrahydropyrrolo[l,2-c]pyrimidine 12 resulted from the decomposition of the intermediate 3H-pyrrole in a retro-Mannich reaction (Scheme 3). 

Deaminomethylation of Mannich bases (path a in Fig. 81), which is actually a retro-Mannich reaction, as it reproduces the same reactants employed in the direct synthesis, has been observed in practically every class of Mannich derivative (Table 22 and Figs. 186, 189 in Chap. V). C-Mannich bases are more stable than the corresponding derivatives, having the aminomethyl group linked to a heteroatom. This has been directly found, for example, in barbituric acid derivatives, although the C-Mannich bases deriving from particularly activated subsU atcs, such as nitroalkanes, also exhibit a remarkable tendency to decompose. "... 

RLsch, N., Langhals, M., and Hohbcrg, T., Triple (Grob) fragmentation. Retro-Mannich reactions of 1-aza-adamantane derivatives. Tetrahedron Lett... 42, 4465, 1991. 

The mechanism of this process was studied in Ref. 296 by the same methods as those employed to examine a Ne-nitrosarco-phaginate. The macrocyclic cobalt(III) complex with a pendant arm, formed at the first stage by a retro-Mannich reaction with loss of a methylene unit, is in equilibrium with a nitronate species. The... 

An interesting pyrrole synthesis involved a retro-Mannich reaction of tropinone derivatives <04EIO1397>. 

An intramolecular photocycloaddition of a vinylogous amide tethered at C-3 of a 1-acylindole has also been achieved in a stereospecific reaction, in which the cyclobutane adduct (332) undergoes a retro-Mannich reaction to give the imino ketone (333), a synthetic precursor of vindorosine (Scheme 104) <90JA8971>. 

Applications in Retro-Mannich Reactions. Treatment of unprotected gramine with NIS results in smooth conversion to 3-iodoindole (eq 20). 3,4-Disubstituted indoles are obtained by combination of the retro-Mannich process with the directed ortho metalation reaction (DoM) or the Negishi cross-coupling protocol. ... 

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