Mannich-type condensation, synthesis

T. Akiyama, J. Takaya, H. Kagoshima, One-Pot Mannich-Type Reaction in Water HBF4 Catalyzed Condensation of Aldehydes, Amines, and Silyl Enolates for the Synthesis of (5-Amino Carbonyl Compounds Synlett. 1999,1426-1428. 

The synthesis of zolpidem began with an alkylation/condensation reaction of amino-pyridine 5 and bromide 6 to give imidazopyridine 7 (Scheme 15.1). Mannich-type reaction with formaldehyde and dimethylamine provided 8. Treatment of 8 with methyliodide to form the quaternary salt 9, followed by reaction with sodium cyanide, gave 10. Acidic hydrolysis followed by reaction of the resultant acid 11 with carbonyldiimidazole (GDI) and dimethylamine afforded zolpidem (1) in 46% overall yield (George et al., 1991 Rossey and Long, 1988). 

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

The chemistry of Mannich bases is implied in important spontaneous reactions involving natural products such as the alkaloids,- where a Mannich-type condensation is a key reaction leading to the biogenesis of the final product, as well as in interesting synthetic methods adopted in the laboratory preparation of natural molecules or of structurally related models. The chemical modification of natural compounds and the synthesis of labeled derivatives for biological studies also constitute relevant applications connected with chemistry of Mannich bases. 

A partial synthesis of voacamine (and voacamidine, XXVI) was carried out by condensing voacangine and vobasinol in refluxing 1.5% methanolic hydrochloric acid 45, 49). This vinylogous Mannich type condensation (Chart VI) has an analogy in the known dimerization of 1-hydroxy-1,2,3,4-tetrahydrocarbazole 45, 50). 

Despite their great structural variety, isoquinoline alkaloids were, for a long time, considered as a vast, but biosynthetically uniform family of natural products, the common key step of their biogenesis always being the Mannich-type condensation of phenylethylamines with aldehydes or a-ketoacids (7). The preparative imitation of this reaction principle, the Pictet-Spengler-type isoquinoline synthesis (2), has been the basis for countless biomimetic alkaloid syntheses (5). 

For example, Porcheddu and co-workers recently reported the synthesis of a series of a,p-unsaturated aldehydes by the dehydrogenative cross-coupling of primary alcohols, which reacted with an amine to form the corresponding imine, followed by a Mannich-type condensation reaction (Scheme 39) [193]. 

Loh, T.-R and Wei, L. L., Novel one-pot Mannich-type reaction in water indium trichloride-catalyzed condensation of aldehydes, amines and silyl enol ethers for the synthesis of amino ketones and esters. Tetrahedron Lett., 1998, 39,323-326. 

Kobayashi, S. Ishitani, H. (1995) A novel Mannich-type reaction in aqueous media. Lanthanide triflate-catalyzed condensation of aldehydes, amines and vinyl ethers for the synthesis of P-amino ketones,Chem. Soc., Chem. Commun., 1379. 

The covalent self-assembly approach in the course of a Mannich-type condensation was used for the synthesis of P,N-containing cyclophanes with an amino-methylphosphine backbone. The condensations in the three-component systems primary phosphine/formaldehyde/secondary diamine with angular di(p-pheny-lene)methane spacer (or bis(4-amino-3-carboxyphenyl)methane) or with linear biphenylene spacers led to the formation of N-containing macrocyclic diphosphines 124 as a result of [2 -I- 2]-condensation (Scheme 12.48). The condensations were performed in DMF at the reagents concentrations of 0.1-0.3 M at 100-110 °C or at ambient temperature in the case of N-pyridylmethyl substituted diamines [122]. 

The total synthesis was achieved in 1954 by Woodward and his collaborators (156). Before this, various unsuccessful attempts had been made to make a start toward a synthesis of strychnine (179, 180, 181, 182,) but these are now of little interest, with the exception of Robinson s idea (182) to emulate the postulated biosynthesis by attempting to synthesize the dialdehyde CCXVI, which then might be induced to cyclize by a combination of Mannich and aldol type condensations to the Wieland-Gumlich aldehyde (LV) the synthesis of CCXVI unfortunately was not realized. Much more recently, however, this idea has been used by van Tamelen et al. (184), who successfully synthesized the dialdehyde CCXVII and converted it in aqueous acetic acid-sodium... 

Compounds of lype 27 and analogous derivaiives such as sulfonamides are frequently used in condensation reactions (defined as amidomcthylations) with formaldehyde and substrates of the same type as those subjected to Mannich synthesis. Yet. the products obtained cannot be strictly considered as Mannich bases, due to their negligible basicity. 

Various types of bis-Mannich bases (Table 32), ranging from kctonic to phenolic and amidic, are suitable for condensation with bis-amines and bis-thiols. As far as bis-amines are eoncemed, besides the compounds 379-381 of Table 31, methylpiperazine 404 is used. An even larger number of bis-thiols (405-409) arc employed in the synthesis of polythioethers. 

In addition to their use in Mannich (and variant) reactions, iminium ions are useful for other cationic type cyclizations. Corey employed a novel tandem iminium ion cyclization as part of an elegant cascade used for the synthesis of aspidophytine. The reaction of tryptamine 292 and dialdehyde 293 in CH3CN at ambient temperature afforded the pentacyclic skeleton of the alkaloid (296 Scheme 54) (99JA6771). Condensation of the free amino functionality of 292 with the dialdehyde produced a dihydropyridinium intermediate 294 that then cyclized onto the indole n-bond to give 295. The iminium ion so produced underwent a second cyclization with the tethered allylsilane moiety to give 296. Protonation of the enamine in 296 provided still another iminium ion (297) that was then reduced with NaCNBH3 to furnish 298 in 66% yield. All of the above reactions could be made to occur in a single pot. 

Of the various imines known to condense with active methylene compounds, a-arylimines have been the most widely used, especially in earlier work, because of their stability, ease of preparation and the absence of enolizable protons. Aliphatic imines containing enolizable protons have broader synthetic applications but their use is more restricted because they are prone to deprotonation and self aldol type condensations. As will be discussed, new methods utilizing Lewis acids and the less basic boron enolates have been devised to overcome the problem of deprotonation. Other innovations that have extended the scope of imine condensations include in situ methods for the preparation of elusive formaldehyde imines (CH2=NR2> and the utilization of A/-heterosubstituted imines (N = Si, O and S) for the synthesis of primary Mannich bases and A(-unsubstituted 3-lactams, available via hydrolysis or reduction of the N—X bond. 

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