Mannich reaction cascade reactions

Scheme 7.106 NHC-catalyzed as3mimetric Michael/Mannich/lactamization cascade reaction of 2-bromoenals with tosyl-protected o-amino aromatic aldimines reported by Hui.

In 2011, the Fukuyama group reported the first total synthesis of (-)-conophylline, whose structure consists of two pentacyclic aspidosperma skeletons (Scheme 13.5) [6]. The two aspidosperma skeletons were both constructed through a similar intramolecular Michael addition/Mannich reaction cascade stfategy, which could produce three new rings and three new stereogenic centers with complete stereoselectivity in just one step. 

SCHEME 2.42 Chiral thiourea-catalyzed Mannich-Michael cascade reaction. 

SCHEME 2.45 Chiral thiourea-catalyzed Mannich-alkylation cascade reaction. 

The isolation of an intermediate revealed that the reaction proceeds via a tandem Mannich-Michael addition pathway. The zinc (II) chloride-promoted cascade reaction starts with a Mannich reaction. For a number of reactions, the Mannich-type intermediate can be isolated if the reaction is stopped by addition of diluted ammonium chloride solution [52,53]. 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

The Mannich reaction is a very common process that occurs in many tandem reaction sequences. For example, the Overman Aza-Cope cascade sequence is terminated by a Mannich reaction (cf. Scheme 35). Several groups have used variants of the Mannich reaction to initiate cascades that lead to the formation of heterocyclic molecules. For example, the Lewis acid-catalyzed intermolecular vinylogous Mannich reaction (01T3221) of silyloxy furan 281 with nitrone 282 produced a diastereomeric mixture (49 3 42 6) of azabicycles 284a-d in 97% combined yield (Scheme 52) (96TA1059). These products arose from an intramolecular Michael addition of the initially formed oxonium ion 283. 

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. 

On the other hand, there is a report regarding a cascade Michael reaction followed by intramolecular nitro-Mannich (aza-Henry) reaction occurring between imides derived from diethyl aminomalonate and nitrostyrenes using thiourea 68a as catalyst (Scheme 7.63). This reaction results in a formal [3 + 2] cycloaddition between these two reagents, with this aminomalonate-derived... 

OH) with aldehydes 9 in the homogeneous conditions (DMF or DMSO) (Scheme 10.1). Furthermore, PEG-supported catalyst 20a could be recovered by precipitation from the DMF solution with ether and reused in the same reactions without reduction of enantiomeric excesses of products 10 (R = OH). It also appeared applicable to asymmetric iminoaldol (Mannich) reactions to afford p-aminoketones 16 (R = Ar) (Scheme 10.3) and to the enantioselective Michael/aldol cascade reaction resulting in the S3mthesis of Wieland-Mischler ketone 28b, an important precursor of some other natural compounds (Scheme 10.6). Diastereo- and enantioselectivities of these reactions were close to the corresponding data for proline-catalysed reactions. 

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). 

Subsequently, the authors extended this reaction to an enantioselective Mannich-cyclisation cascade using tridentate DBFox-Mg(n) as catalyst for the preparation of protected anh -a,p-diamino acids. After examining various BOX ligands in the process, they found that DBFox 39h could deliver the required adducts 71 in good to excellent yields (63-99%), diastereos-electivities (7 93-32 68) as well as enantioselectivities (84-99% ee). The scope of the reaction was rather broad and a variety of aryl-, heteroaiyl-, alkenyl-, and allqrl-derived imines could be tolerated (Scheme 3.22). 

Optically active trifluoromethyl-substituted tetrahydroimidazo[l, 5-c] quinazoline derivatives 44 were synthesized by Zhao and coworkers via a diastereo- and enantioselective Mannich-type cyclization cascade reaction of a-aryl isocyanoacetates and trifluoromethyl-substituted cyclic ketimines, using a multihydrogen-bonding donor squaramide/AgOAc cooperative catalytic system in THF at 0°C (Scheme 30) (140L4566). The products were obtained in 76—99% yield with a diastereomeric ratio of greater than 15 1 and 58-98% enantiomeric excess. 

In the intensively studied field of multicomponent reactions (MCRs), one can highlight several interesting cascades involving successive C-N and C-C bond formations. It is important to note that, although the majority of these sequences such as the Hantzsch, the Biginelli, or the Mannich reactions are known for more than one century, their organocatalytic enantioselective versions have been disclosed only very recently. 

One of the first examples of an enamine-catalyzed cascade reaction for the synthesis of a complex alkaloid was reported by Itoh et al. (179). Reaction of the dihydrocarboline 194 with enone 195 in the presence of (5)-12 (7 days) gave the tetracycle 196 as a single diastereomer and in excellent enantiopurity (99%). This reaction can be described best as an enamine-catalyzed Mannich-Michael domino addition. Further manipulations then gave access to the indole alkaloid ent-dihydrocorynantheol (197) in an elegant and facile manner. As depicted in... 

The Overman pyrrolidine synthesis is a tandem reaction, or cascade, used to generate acylpyrrolidine derivatives. This process begins with condensation of an allylic alcohol/ether-containing secondary homoallylic amine with an aldehyde, followed by an aza-Cope rearrangement and subsequent Mannich reaction. Commonly, this reaction is run in refluxing benzene with an acidic additive, such as c/-10-camphorsulfonic acid (CSA). 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

See, for instances (a) S. Santra, R R. Andreana, Org. Lett. 2007, 9, 5035-5038. A one-pot, microwave-influenced synthesis of diverse small molecules by multicomponent reaction cascades, (b) M. Presset, Y. Coquerel, J. Rodriguez, Org. Lett. 2009, 11, 5706-5709. Microwave-assisted domino and multi-component reactions with cyclic acyUcetenes expeditious syntheses of oxazinones and oxazindiones. (c) W.-J. Hao, B. Jiang, S.-J. Tu, X.-D. Cao, S.-S. Wu, S. Yan, X.-H. Zhang, Z.-G. Han, F. Shi, Org. Biomol. Chem. 2009, 7,1410-1414. A new mild base-catalyzed Mannich reaction of hetero-arylamines in water highly efficient stereoselective synthesis of 3-aminoketones under microwave heating, (d) P. Nun, J. Martinez, F. Lamaty, Synthesis 2010, 2063-2068. Microwave-assisted neat procedure for the Petasis reaction. 

---