Double Mannich reaction

In 2003, Williams and Mander reported a method designed to access the hetisine alkaloids (Scheme 1.3) [27]. This approach, based upon a previously disclosed strategy by Shimizu et al. [28], relied on arylation of a bridgehead carbon via a carbocation intermediate in the key step. Beginning with (1-keto ester 46, double Mannich reaction provided piperidine 47. Following a straightforward sequence, piperidine 47 was transformed to the pivotal bromide intermediate 48. In the key step, bromide 48 was treated with silver (I) 2,4,6-trinitrobenzenesulfonate in nitro-methane (optimized conditions) to provide 49 as the most advanced intermediate of the study, in 54 % yield. 

Mannich and double-Mannich reaction with [l,2,4]triazolo[3,4- ]benzothiazole-3-thione 178 and />-toluidine, phenylenediamine, and benzidine, in the presence of formaldehyde, gave compounds 72-74 (unreported yields) (Scheme 3) <2002MI3, 2002MI4>. 

A similar vinylogous Mannich reaction has been used by Martin in the total syntheses of the heteroyohimboid alkaloids (—)-ajmalicine and (—)-tetrahydroalstonine <1995JOC3236>. An attempted synthesis of an opioid analgesic 2,4-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one-l,5-dicarboxylate (piperidone) by a double Mannich reaction of oxoglutarate, 2 equiv of phenylacetaldehyde, and methylamine did not give the expected product but instead gave rise to an unexpected [l,6]naphthyridine derivative (Scheme 57) <1998PHA442>. 

Treatment of the A-substituted piperidinones 317 with primary amines and formaldehyde gave bispidinones 198. This double Mannich reaction provided a valuable and versatile approach to a large number of bispidinone derivatives. The reaction took place with a wide variety of primary amines and provided both symmetric and asymmetric bispidinones depending on whether the primary amine and the piperidinone nitrogen bore the same or different substituents. 

Treatment of iV,iV-bis(ethoxymethyl)isopropylamine 548 with pyran-4-one 547 through a double-Mannich reaction, Lewis acid promoted, yielded the 1,5-oxazocine 415 in 75% yield (Equation 25) <2006OL3399>. 

Afsah, E. M Hammouda, M., and Abou-El-zahab, M. M., A study of the double Mannich reaction with 1,3-diphenylacetonc, Monatsh. Chem.. 115,581, 1984. 

In more recent applications, Takajo and Kambe have reported a new synthesis of perhydropyrimid-ines (90) by a double Mannich reaction (one step is intramolecular) using hydrobenzamide (87) and methyl cyanoacetate (89 equation 15). The reaction is general for other highly acidic methylene compounds including malononitrile, dimethyl malonate and nitroethane. In some cases, the intramolecular Mannich step is slow and side products arising from decomposition of the initial adduct are formed. This phenomenon is temperature dependent, indicating that intermediates in the reaction are formed reversibly. 

The pool of C H acidic components is restricted to compounds that allow a double Mannich reaction. Most common are esters of acetonedicarbonic acid, especially dimethyl acetonedicarboxylate, which is the general substrate for the... 

Disubstituted tetrahydro-r-triazolo[3,4-3][l,3,5]thiadiazines 272 have been synthesized in 50-85% yield by the double Mannich reaction of 3-aryl-5-mercapto-l,2,4-triazoles 273 with various aromatic amines and formaldehyde in the presence of ethanolic HCl, as shown in Scheme 57 <1996MOL89>. 

When the 1,3-indanedione 1-phenylhydrazone (89) was subjected to a double Mannich reaction using benzylamine or methylamine and formaldehyde in the presence of a small amount of acetic acid, it afforded (60-65% yield) the indano-1,2,4-triazepines (90) (Scheme 14) <90ZN(B)80>. The NMR spectra indicate that (90) existed in solution as mixtures of keto and enol tautomers. Similarly,... 

This reaction was first reported by Petrenko-Kritschenko in 1906. It is the preparation of piperidone via a double Mannich Reaction from acetonedicarboxylic ester, two equivalents of aldehyde, and ammonia (or a primary amine), and is known as the Petrenko-Kritschenko piperidone synthesis. In this reaction, the mixture of reaction components is usually refluxed in an aqueous or alcoholic solution, and the resulting product is difficult to purify. It has been found that the addition of acid to the reaction medium is useful for this reaction.2... 

This reaction was first reported by Robinson in 1917 and subsequently improved by Schopf in 1935. It is an ingenious one-pot multicomponent synthesis of tropinone from succindialdehyde, acetonedicarboxylic acid and methylamine in aqueous solution involving a double Mannich Reaction This reaction is thus known as the Robinson tropinone synthesis," Robinson synthesis, " Robinson-Schopf reaction,Robinson-Schopf condensation, or Robinson condensation." It has been reported that the Robinson tropinone synthesis can take place without any racemization at the stereogenic center adjacent to the aldehyde group, as demonstrated by the formation of L-a/to-teloidinone from D-tartaraldehyde, and c-a/to-teloidinone from i-tartaraldehyde respectively." ... 

Kraus and Shi used condensation reactions for the assembly of precursors to the quasi-Favorskii rearrangement. Reaction of the bromoketoester 83 with ethylamine and formaldehyde gave 84, the result of a double Mannich reaction fScheme 7.22T Under acidic conditions, methyl vinyl ketone combined with 83 to give the annulation product 87. Each of these products, 84 and 87, was a good substrate for the quasi-Favorskii rearrangement. Ketone 84 reacted with the enolate of acetylcyclohexene (85) to produce 86 in 60% yield. Ketone 87,... 

Piperidones (19) have been prepared from ketones (MeCOCH2R) and aromatic imines (Ar -N=CHAr ) via a double Mannich reaction and tandem cyclization. The l2-induced room temperature reaction is highly stereoselective, giving only one of four possible isomers. Chelation and hydrogen-bonding effects have been invoked to explain the specificity(g)... 

A silica tungstic acid (STA)-catalyzed Knoevenagel condensation/Michael addition/double Mannich reaction... 

In 2009, List and coworkers reported a highly diastereo and enantioselective proline-catalyzed double Mannich reaction of acetaldehyde with A-Boc imines [3], The treatment of 1 equiv of acetaldehyde with 3 equiv of A-Boc imine derived from benzaldehyde in the presence of 20 mol% of L-Pro produced the double Mannich adduct 2 in quantitative yield and with exceptionally high diastereo and enantiose-lectivities (dr > 99 1, ee > 99%) (Scheme 12.2). The reaction was performed with a variety of A-Boc imines, namely aromatic and heteroaromatic substituted imines, and furnished the products in excellent yields (76-99%) and with similar stereoselectivities (dr > 99 1, ee > 99%). Even the unstable isovaleraldehyde-derived A-Boc imine gave the double Mannich adduct stereoselectively, albeit with a moderate yield (30%). 

The one-pot cross double Mannich reactions with two different imines led to the formation of a complex mixture containing Mannich adducts, homocoupling products, as well as the desired cross-Mannich product. In order to circumvent this synthetic problem, the desired cross-Mannich targets were prepared by isolating the initial mono-addition products, which were then engaged in a second L-Pro-catalyzed Mannich reaction with a different N-Boc imine. Under these conditions, the cross-Mannich compounds were obtained in reasonably good yields and high selectivities. 

In 2013, Mamoka and coworkers published a one-pot cross double Mannich reaction of acetaldehyde catalyzed by a binaphthyl-based aminosulfonamide [4]. The functionalized diamines were obtained as a single stereoisomer in moderate yields (45-57%) with excellent enantioselectivity (99%). The procedure was also extended to other electrophiles such as nitrosobenzene. Two examples of a one-pot Mannich reaction-aminoxylation were described, and the yn-p-amino-a-hydroxyaldehydes were obtained with excellent stereoselectivity (dr > 20 1, ee 99%). These reactions were performed by using a large excess of acetaldehyde to produce the single Mannich adduct, and the excess amount of acetaldehyde was removed by evaporation before the addition of the second electrophile. This operational procedure lowers the synthetic appeal of this strategy, and, as a result, it is in the limit of the field of MBFTs. 

Chandler, C., Galzerano, R, Machrowska, A., List, B. (2009). The proline-catalyzed double Mannich reaction of acetaldehyde with AI-Boc imines. Angewandte Chemie International Edition, 48, 1978-1980. 

Kano, T., Sakamoto, R., Yamaguchi, Y., Ito, K., Maruoka, K. (2013). One-pot cross double-Mannich reaction of acetaldehyde catalyzed by a binaphthyl-based amino sulfonamide. Chemical Communications, 49, 1118-1120. 

Scheme 28.8 Double Mannich reaction of acetaldehyde with imine.

Moreover, enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 1.11). The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-Cj-symmetric p,p -diaminoaldehydes 37 with extremely high stereoselectivities (>99 1 dr, >99% ee) [13], A similar approach with ketones was also realized [14],... 

---