Mannich-cyclisation

Tazettine. The elegant method [99] for the construction of cis-arylhydroindoles B (X = H) (Scheme 55) involving tandem azaCope rearrangement - Mannich cyclisation from appropriate cyclopentane A (X = H) was examined for the substrate A (X = SiR3 X/Ar Irons) as means of possible entiy into cis -arylhydroindole B (X = SiR3 X/Ar irons) potentially capable of subsequent direct conversion into pretazettine. 

If the molecule is too rigid for the Mannich cyclisation to occur easily, it is possible to carry it out as a separate step. Overman s approach to gelsemine, a very difficult target, involves an anionic aza-Cope rearrangement on 201 and the trapping of the enolate.31 The resulting ketone 202 is cyclised in acidic solution. Evidently the addition of the enol to the protonated imine goes better than the cyclisation of the enolate onto the neutral imine when the final product is as strained as 203. 

The standard, acidic Mannich conditions do not allow simple substitutions of the imidazole and thiazole systems with the much less basic oxazole an intramolecular Mannich cyclisation has been described. ... 

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). 

Mammary gland tumor, 991 Management, 543 Mandelin, 535 Manduca sexta, 4096 Mangifera indica, 1553 Mangiferin, 1553 Mannich cyclisation, 50 Mannosyl transferases (MTs), 1270 Manzamine-type, 1293 MAO. See Monoamine oxidase (MAO) MAPKs. See Mitogen-activated protein kinases (MAPKs)... 

Scheme 2.22 Three-component domino Michael-Mannich-cyclisation reaction catalysed by a combination of chiral diphenylprolinol triethylsilyl ether and a chiral thiourea.

Even if organocatalysis is a common activation process in biological transformations, this concept has only recently been developed for chemical applications. During the last decade, achiral ureas and thioureas have been used in allylation reactions [146], the Bayhs-Hillman reaction [147] and the Claisen rearrangement [148]. Chiral organocatalysis can be achieved with optically active ureas and thioureas for asymmetric C - C bond-forming reactions such as the Strecker reaction (Sect. 5.1), Mannich reactions (Sect. 5.2), phosphorylation reactions (Sect. 5.3), Michael reactions (Sect. 5.4) and Diels-Alder cyclisations (Sect. 5.6). Finally, deprotonated chiral thioureas were used as chiral bases (Sect. 5.7). 

Tin and HCl reduce out the ben/.ylic OH from (43) in high yield.The Mannich base (45) decomposes to (41) simply on heating. Cyanide addition gives (46) which can be hydrolysed to (40), but a short cut is to hydrolyse to amide (47) and reduce out the carbonyl group by the Clemmensen method (Table T 24.1). Under these conditions the amide is hydrolysed to the acid. Cyclisation to (38) occurs with strong acid, acid anhydrides, or by AlClg-catalysed reaction of the acid chloride. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

The forward synthetic sequence would therefore involve the Michael reaction of 2-methylcyclopentane-l,3-dione with methyl vinyl ketone to give (20), followed by cyclisation to the hydroxyketone (19), and then dehydration to the target molecule (13a). The overall process of addition and cyclisation is known as the Robinson annelation reaction.3 In this preparative example (Expt 7.6) the methyl vinyl ketone is used directly under conditions which minimise its polymerisation 48 it should be noted, however, that many literature examples of the annelation reaction use Mannich bases or the corresponding methiodides as an in situ source of the a, /J-unsaturated carbonyl component (see Section 5.18.2, p. 801). 

Phosphorus-containing Ring Systems. - A range of new chiral oxazaphospholidine oxides 266 and 267 have been synthesised and used as catalysts in asymmetric reductions of ketones with diborane. Mannich-type cyclisation reactions of 5-amino-3-benzylthio-4-cyano(ethoxycarbonyl)pyrazoles with dichlorophenylphosphine and aromatic aldehydes in the presence of cation exchange resin have been used to prepare a number of 6-oxo-6-phospha-4,5,6-trihydroimidazolo[l,2-b]pyrazoles, e.g. 268. Some of these compounds have herbicidal activity and this report is typical of a number of similar ones in the Chinese literature. A number of metallocycles, e.g. 269, have been reported as products from reactions of transient zirconocene-benzyne intermediates with phosphaimines followed by sulfuration or selenation. ... 

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). 

In formic acid, the enamine is protonated on carbon to give the very electrophilic immonium ion 208 which cyclises in conformation onto the enol 208a in an intramolecular Mannich reaction to give the bicyclic skeleton 203 required for gelsemine. 

Stereochemical control in the double conjugate addition Tandem Reactions as Polymerisation Terminated by Cyclisation The MIMIRC sequence with vinylphosphonium salts Tuning the MIMIRC sequence with different Michael acceptors Heterocycles by Tandem Conjugate Additions Tandem conjugate addition and Mannich reaction Tandem Conjugate Addition and Aldol Reaction... 

It is initially puzzling that it is not necessary to hydrolyse the acetal before the Mannich reaction. Under the acidic conditions, the acetal is in equilibrium with the end ether and this is reactive enough to combine with the very electrophilic iminium ion 102. The stereochemistry of the product is determined in this cyclisation step and simply ensures that the two five-membered rings are cis fused. 

We have spent some time over this synthesis as it is a beautiful example of convergent use of enantiomerically pure starting materials brought together with a tandem Mannich/vinyl silane cyclisation at its core. 

Conducted in an intramolecular sense, Mannich reactions have been much used for the construction of tetrahydro-P-carbolines. ° Tryptamines carrying a 2-carboxylic acid group, which can be conveniently prepared (20.16.6.3), but are not easily decarboxylated as such, undergo cyclising Mannich condensation with aldehydes and ketones, with loss of the carbon dioxide in a final step. ° ... 

These cyclisations may proceed by direct electrophilic attack at the a-position, or by way of p-attack, then rearrangement. It may be significant that Mannich processes, as opposed to the alkylations discussed in Section 20.1.1.6, are reversible, which would allow a slower, direct a-substitution to provide the principal route to the a-substituted structure. 

Its synthesis is based on the cyclisation of the keto Mannich base salt 9 with hydrazine hydrate to yield 3-(4-chlorophenyl)-2-pyrazoline (10), which is then carbamoylated with 4-chlorophenyl-isocyanate, as shown is Scheme 1.16. 

Earlier syntheses of quinolizidines involved Mannich reactions of pelletierine. In a new approach, applied to the synthesis of (+)-vertaline (Scheme 6), allylic strain controls the stereochemical course of cyclisation of the N-acyliminium ion (40) the... 

The Mannich method of control (Chapter 20) can be used here—the vinyl ketone being released in the reaaion mixture. Cyclisation of (36) is unambiguous as the alternative product (38) cannot dehydrate to a conjugated enone. Hydrolysis and decarboxylation occur under the reaction conditions. 

Mannich control is unnecessary here as (16) has only one enolisable proton, though a weak base is used to prevent Cannizzaro reduction of (15). We need to make conditions for cyclisation as favourable as possible so the OH group in (15) is converted into a better leaving group and MeOH is added as the more reactive MeO. ... 

Arylethanamines react with aldehydes easily and in good yields to give imines. 1,2,3,4-Tetrahydroisoquinolines result from their cyclisation with acid catalysis. Note that the lower oxidation level imine, versus amide, leads to a tetrahydro- not a dihydroisoquinoline. After protonation of the imine, a Mannich-type electrophile is generated since these are intrinsically less electrophilic than the intermediates in Bischler-Napieralski closure, a strong activating substituent must be present, and appropriately sited on the aromatic ring, for efficient ring closure. 

Imidazoles react with Mannich electrophiles at nitrogen, however the overall effect of Mannich C-substitution has been found in base-catalysed cyclisation of histamine Schiff bases closure does not take place in the absence of base and it must be the imidazolyl anion which reacts intramolecularly with the side-chain imine. " ... 

Phosphorodithioic adds have been prepared according to an improved synthesis of 3,3 -disubstituted BINOL derivatives (226-231). In preliminary experiments, these new Bronsted adds were tested as organocatalysts in three reactions. They promoted the Nazarov cyclisation with mixed selec-tivities, the Mannich reaction with good enantioselectivity and they catalyzed efficiently the alkylation of iV-acyliminium with enol silyl ether. ... 

The reaction was proposed to occur via an enamine-intermediate, which attacks the aldimines to generate q M-Mannich-type intermediates (Scheme 5.48). Cyclisation to produce the hemiaminal, followed by reductive amination, generates the functionalised pyrrolidine products stereoselectively. 

Prolinol silyl ether catalysts were also able to control the Mannich reaction of acetaldehyde. Xu and coworkers utilised Michael adducts of aldehydes with nitroalkenes in the subsequent Mannich-type reaction with imines followed by cyclisation. Highly substituted chiral piperidines were formed. Suitable imines for organocatalytic Mannich reactions can also be generated in situ from amido sulfones (Scheme 8.34). ... 

In addition, a highly diastereo- and enantioselective synthesis of 2,3-disubstituted tetrahydropyridines was accomplished via a proline-mediated cascade Mannich-type/intramolecular cyclisation reaction from preformed... 

Scheme 3.6 L-Proline-catalysed domino Mannich-type/intramolecular cyclisation reactions.

Scheme 7.40 Three-component domino cyclisation-Mannich-type-acetalisation reaction catalysed by chiral phosphoric acid catalysis and gold catalysis.

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