Mannich reaction, with acetone

Malonic ester syntheses, 30, 7 Malononitrile, 37, 53 Malonyl dichloride, 33, 20 Mandelic acid, 36, 3 Mandelic acid, />-bromo, 35,11 Mannich reaction, with acetone, 37,18 Mercaptoacetaldehyde, diethyl ACETAL, 35, 51... 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

A closely related synthesis of symmetrically substituted bispidinones 19a-w is provided by the Mannich reaction with acetone derivatives 319, paraformaldehyde, and the acetate salts of various amines. Such a reaction is formally a C2N + C2N + 2C synthesis but is reported here because of its relationship to the above bispidinone synthesis. In this case the intermediate piperidinone cannot be isolated but once formed, it reacted with the primary amine and formaldehyde to give the eight-membered ring <1995T2055, 19970M1167>. Similarly, the diamine 320 reacted with dibenzyl ketone and formaldehyde to give the macrocycle 321 in 48% yield <1995T4819>. 

Mannich reaction, with acetone, 37, 18 Mercaptoacetaldehyde, diethyl ACETAL, 35, SI... 

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. 

Elimination of R NH. Cardwell showed that the Mannich reaction of acetone with formaldehyde and dimethylamine gives the unsymmetrical product (1), and that... 

In 2004, Hayashi and coworkers found trans-4-TBSO-(5)-proline 29 to be more active than the parent proline organocatalyst for the asymmetric a-aminojylation of enolisable aldehydes 8 (R = H) or cyclic ketones 11 (X=-CH2-, -C(Me)2-, -S-) with nitrosobenzene to prepare optically pure (>99% ee) hydrojylamine derivatives 12 or 13 in 50-76% yield (Scheme 10.2). Compound 29 (30 mol%) also efficiently catalysed the a-aminojylation/intramolecular Michael cascade reaction of cyclohexenones 34 with nitrosobenzene to afford bicyclic compounds 35 with veiy high enantioselectivity (Scheme 10.7). Furthermore, in the presence of organocatalyst 29, three-component Mannich reactions of acetone 8 (R = Me, R = H) with benzaldehyde derivatives 9 (R = Ar) and 4-metho3yaniline produced the corresponding enantiomers (90-98% ee) of p-amino ketones 16 in mild experimental conditions (—20 °C) (Scheme 10.3). 

List also reported on the synthesis of iV-Boc protected aldimines employing proline as the catalyst, and found that acetone could be used as Mannich donor (73% yield, ee >98%) [20]. The latter gronp nicely exemplified the viability of using Boc-protected aldimines 23a-e in Mannich reactions with aldehydes 2b, 2d, 2f to prepare a series of p-aminoaldehydes 25a-g in high yield and excellent selectivities (Scheme 5.14) [21], An important difference with the A-aryl-protected imines 10 is that due to the more difficult formation of A-acylated imines, preformation of the imines is required and that three-component Mannich reactions are not possible. 

Functional Group Modification. The cyclopropanone derivative (623a) has been shown to give a Mannich-type reaction with acetone or dimethyl malonate, but it fails to react with many other well-known Mannich reagents. A... 

The reaction can be carried out by heating TNT in a basic solution of aqueous formaldehyde. TNT is only poorly soluble in this solution, however. Better results are obtained when acetone is used as a cosolvent. TNT undergoes the Mannich reaction with formaldehyde and various secondary amines according to the equation ... 

In 2006 Kantam et al. [54] reported two- and three-component asymmetric Mannich reactions catalyzed by L-prohne in DMSO under ultrasonic conditions. Initially, the reaction with acetone was studied, and after sonication for 1 h the Mannich product was obtained in 50% yield and surprisingly low enantioselectiv-ity (36% ee) (Scheme 21.24). Under conventional conditions with stirring the reaction afforded the corresponding product with similar yield after 12 h and significantly higher enantioselectivity [55]. In this reaction the ultrasonic experiment shows a significant increase in reaction rate. An analogous reaction with cyclohexanone resulted in a much lower yield (15%) [54]. 

Tritiated formaldehyde is also useful in Mannich reactions. Examples of such applications include the preparation of the topoisomerase-1 inhibitor 364 by condensation of tritiated formaldehyde and dimethylamine with 10-hydroxycamptothecin 1363). the reaction with acetone and diethylamine to give 4-diethylamino-4-[ H2]butan-2-one 365 which was further converted upon heating with thebaine (366) to the morphine derivative 367 (specific activity of 46 Ci/mol). Furthermore, condensation of aqueous deuterated formaldehyde with allyltrimethylsilane to prepare the 2,6-doubly labeled piperidine 368. as indicated , would be expected to work equally well with tritiated formaldehyde. 

In 2007 a very important article was published by Kappe [35], a well-known specialist in the field of the microwave research. His group re-examined the Marmich and aldol reactions presented above and carefully investigated the differences between conventional and microwave heating (results presented in Schemes 21.10-21.12). Moreover, the Mannich reaction of acetone with the PMP-protected imino ester of ethyl glyoxylate was studied (Scheme 21.13). In this case the obtained results, under MW (49 W or 270 W with Uquid cooling) at 60 C for lOmin, were very similar in terms of yield and enantioselectivity to those obtained for the reaction performed in an oil bath at the same temperature and reaction time (90-92%, >99% ee). Similar results with microwave dielectric heating and conventional thermal heating were also obtained for the Mannich and aldol reactions presented in Schemes 21.10-21.12 [35]. 

Other modifications of the polyamines include limited addition of alkylene oxide to yield the corresponding hydroxyalkyl derivatives (225) and cyanoethylation of DETA or TETA, usuaHy by reaction with acrylonitrile [107-13-1/, to give derivatives providing longer pot Hfe and better wetting of glass (226). Also included are ketimines, made by the reaction of EDA with acetone for example. These derivatives can also be hydrogenated, as in the case of the equimolar adducts of DETA and methyl isobutyl ketone [108-10-1] or methyl isoamyl ketone [110-12-3] (221 or used as is to provide moisture cure performance. Mannich bases prepared from a phenol, formaldehyde and a polyamine are also used, such as the hardener prepared from cresol, DETA, and formaldehyde (228). Other modifications of polyamines for use as epoxy hardeners include reaction with aldehydes (229), epoxidized fatty nitriles (230), aromatic monoisocyanates (231), or propylene sulfide [1072-43-1] (232). 

Pyrazolones show a great variety of reactions with carbonyl compounds (B-76MI40402). For instance, antipyrine is 4-hydroxymethylated by formaldehyde and it also undergoes the Mannich reaction. Tautomerizable 2-pyrazolin-5-ones react with aldehydes to yield compound (324) and with acetone to form 4-isopropylidene derivatives or dimers (Scheme 8 Section 4.02.1.4.10). 

The synthesis of tropinone 14, a precursor of atropine and related compounds, is a classical example. In 1917 Robinson has prepared tropinone 14 by a Mannich reaction of succindialdehyde 11 and methylamine 12 with acetone 13 better yields of tropinone were obtained when he used the calcium salt of acetonedicar-boxylic acid instead of acetone. Modern variants are aimed at control of regio-and stereoselectivity of the Mannich reaction. ... 

Methyl vinyl ketone 2 tends to polymerize, especially in the presence of a strong base the yield of annulation product is therefore often low. A methyl vinyl ketone precursor, e.g. 6, is often employed, from which the Michael acceptor 2 is generated in situ, upon treatment with a base. The quaternary ammonium salt 6 can be obtained by reaction of the tertiary amine 5, which in turn is prepared from acetone, formaldehyde and diethylamine in a Mannich reaction. 

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 Mannich reaction is best discussed via an example. A mixture of dimethylamine, formaldehyde and acetone under mild acidic conditions gives N,N-dimethyl-4-aminobutan-2-one. This is a two-stage process, beginning with the formation of an iminium cation from the amine and the more reactive of the two carbonyl compounds, in this case the aldehyde. This iminium cation then acts as the electrophile for addition of the nucleophile acetone. Now it would be nice if we could use the enolate anion as the nucleophile, as in the other reactions we have looked at, but under the mild acidic conditions we cannot have an anion, and the nucleophile must be portrayed as the enol tautomer of acetone. The addition is then unspectacular, and, after loss of a proton from the carbonyl, we are left with the product. 

Three years after the discovery of the asymmetric BINOL phosphate-catalyzed Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended these transformations to the use of simple ketones as nucleophiles (Scheme 25) [44], Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence of chiral phosphoric acids (R)-3c, (/ )-14b, or (/ )-14c (0.5-5 mol%, R = Ph, 4-Cl-CgH ) to give P-amino carbonyl compounds 69 or 70 in good yields (42 to >99%), flnfi-diastereoselectivities (3 1-49 1), and enantioselectivities (72-98% ee). 

It combines with the electrophilic component (acetone in this case) to make it even more electrophilic. We met this previously in the Mannich reaction (frames 248-250). 

An important feature of this reaction is that in contrast to most other catalytic asymmetric Mannich reactions, a-unbranched aldehydes are efficient electrophiles in the proline-catalyzed reaction. In addition, with hydroxy acetone as a donor, the corresponding syn-l, 2-aminoalcohols are furnished with high chemo-, regio-, diastereo-, and enantioselectivities. The produced ketones 14 can be further converted to 4-substituted 2-oxazolidinones 17 and /i-aminoalcohol derivatives 18 in a straightforward manner via Baeyer-Villiger oxidation (Scheme 9.4) [5]. 

A study by Hayashi et al. demonstrates that less reactive electron-rich aromatic aldehydes efficiently undergo Mannich reactions under high pressure induced by water freezing [8], For instance, in the Mannich reaction of p-anisaldehyde, 3,4-dimethoxybenzaldehyde or N-acetyl-(4-formyl)aniline, with acetone and p-anisidine, good yields (61-99%) and excellent enantioselectivities (92-97%) have been obtained under water-freezing high-pressure conditions while there is no reaction at room temperature at 0.1 MPa (Scheme 9.6). 

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