Mannich Intermolecular

In one of the few publications not directly connected with the synthesis of alkaloids, an original method for the formation of hexahydroazocino[4,3-fc]-indoles using a Mannich intermolecular reaction of the corresponding 2-(N-i -aminobutyl)indoles 50 has been reported (Scheme 14 87JCS(P1)1599). 

Scheme 7 syn-Diastereoselective intermolecular hydrogen-mediated Mannich coupling employing cationic Rh catalysts ligated by tri-2-furylphosphine... 

The structure of cuscohygrine arises by an intermolecular Mannich reaction involving a second /V-methyl-A1 -pyrrolinium cation (Figure 6.3). 

The intermolecular Mannich reaction combines an aldehyde, an amine and an enolizable carbonyl compound for the one-pot synthesis of yfi-amino ketones or... 

C-H activation-Cope rearrangement, 10, 177 Claisen condensation equivalent, 10, 174 Claisen rearrangement equivalent, 10, 176 enolate alkylation equivalent, 10, 171 Mannich reaction equivalent, 10, 174 as strategic reaction, 10, 171 intermolecular C-H insertion, C-H activation-Cope rearrangement as strategic reaction, 10, 178... 

Surprisingly, the catalytic potential of proline (1) in asymmetric aldol reactions was not explored further until recently. List et al. reported pioneering studies in 2000 on intermolecular aldol reactions [14, 15]. For example, acetone can be added to a variety of aldehydes, affording the corresponding aldols in excellent yields and enantiomeric purity. The example of iso-butyraldehyde as acceptor is shown in Scheme 1.4. In this example, the product aldol 13 was obtained in 97% isolated yield and with 96% ee [14, 15]. The remarkable chemo- and enantioselectivity observed by List et al. triggered massive further research activity in proline-catalyzed aldol, Mannich, Michael, and related reactions. In the same year, MacMillan et al. reported that the phenylalanine-derived secondary amine 5 catalyzes the Diels-Alder reaction of a,/>-un saturated aldehydes with enantioselectivity up to 94% (Scheme 1.4) [16]. This initial report by MacMillan et al. was followed by numerous further applications of the catalyst 5 and related secondary amines. 

Alternative synthetic techniques towards TB derivatives were reported by Becker (93TL1889) and Cekavicus (01TL4239). Becker prepared a highly functionalized TB derivative by heating methyl 5-chloro-4-[(ethoxyoxoacetyl)amino]-2-methoxybenzo-ate in DMSO at 180°C. Cekavicus reported that the novel heterocyclic system 3 arose via the intermolecular Mannich reaction of l,l-dioxo-l,2-dihydro-ben-zo[i]thiophen-3-one (Scheme 4). 

Enamine catalysis using proline or related catalysts has now been applied to both intermolecular and intramolecular nucleophilic addition reactions with a variety of electrophiles. In addition to carbonyl compounds (C = O), these include imines (C = N) in Mannich reactions (List 2000 List et al. 2002 Hayashi et al. 2003a Cordova et al. 2002c ... 

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 IHBs of ort/zo-methylamino 38 and orf/zo-iminophenols 39 deserve interest since the amino and imino nitrogens are among the most basic atoms in intermolecular associations of phenols (see Section VILA). Indeed in orf/zo-Mannich bases (38) an intramolecular proton transfer OH- -N O- -HN+ is observed" " when the... 

Cinchona alkaloids such as 121 possess a nucleophilic quinuclidine structure and can act as versatile Lewis bases to react with ketenes generated in situ from acyl halides in the presence of an add scavenger. By acting as nucleophiles, the resulting ketene enolates can react intermolecularly [53] or intramolecularly [54] with electrophilic C=0 or C=N bonds to deliver formal [2 + 2]-cycloadducts, such as chiral P-lactones or [1-lactams, via aldol (or Mannich)-i intramolecular cydization sequence reactions (Scheme 8.46). The nucleophilic ammonium enolate can also read with energetic... 

In a closely related approach, thermal cyclisation of the Mannich bases (110) to benz[a]acridines occurs directly by an intermolecular process (J.L. Asherson. 0.Bilgic and D.W. Young, J. chem. Soc. Perkin I, 1981, 3041). 

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. 

Two other methods toward the manzamines have been reported recently. A preliminary report by Baldwin s group at Oxford of a biomimetic approach described the preparation of a key tricycle, which bears a resemblance to likely natural product precursors to the manzamines (153). A multistep synthesis from Overman s group at the University of California at Irvine, featuring an intermolecular Mannich reaction, starts from D-(-)quinic acid, thus setting the absolute stereochemistry (154). 

In connection with this special interest present phenolic Mannich bases (PMBs) due to two types of reactive groups, such as phenolic hydroxyl and amine, connected with intermolecular hydrogen bonds. Depending on their amino groups, PMBs can be used as hardeners for cold and hot curing. 

The various methods of generating o-quinone methides,4-5 including the thermal or (Lewis) acid-catalyzed elimination of a phenol Mannich base,149 150-160-161163 the thermal or (Lewis) acid-catalyzed dehydration of an o-hydroxybenzyl alcohol (ether),147-149-151-153-156-157-162-163-165-168 171-175-178-183 the thermal 1,5-hydride shift of an o-hydroxy styrene,171-173 175 178-183 the thermal dissociation of the corresponding spirochromane dimer,158 163-164,166 oxidation of substituted o-alkylphenols,152-170 and the thermal or photochemical-promoted cheletropic extrusion154-155 159 of carbon monoxide, carbon dioxide, or sulfur dioxide (Scheme 7-III), as well as their subsequent in situ participation in regiospecific, intermolecular [4 + 2] cycloadditions with simple olefins and acetylenes,147 149-151 152 153159 162-164... 

Scheme 7.47 Tandem conjugate reduction/intermolecular Mannich reaction.

The scope of this chapter does not allow nor attempt a comprehensive account of all developed processes to date. A detailed summary, in particular of aldol, Mannich, or ot-functionalisation reactions, can be found in excellent reviews written on the topic." Barbas and List reported an asymmetric, direct, intermolecular aldol reaction of acetones and aldehydes (Scheme 5.4), presumably via enamine formation of proline and acetone. As compared to its metal-catalysed alternatives, no preformation of the respective enolate is required, a mode of action that mimics metal-free aldolase enzymes. ... 

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