Mannich bases addition reactions

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

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). 

Addition of ( )-enamines 3, derived from aldehydes and ketones, to various benzylideneimini-um salts 2 has been investigated. The reaction exclusively gives the Mannich bases anti-4 in good to excellent yield (72-94%). Therefore, this method provides an efficient and highly stereoselective route to /i-amino ketones and aldehydes1415. 

In this reaction, methyl groups are cleaved in preference to other saturated alkyl groups. A similar reaction takes place between a Mannich base (see 16-15) and a secondary amine, where the mechanism is elimination-addition (see p. 430). See also 19-5. 

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. 

The reaction between trialkylboranes and enones has found some interesting synthetic applications. An example is the preparation of prostaglandin precursors from exo-methylene cyclopentanone, generated in situ from a Mannich base. After dehydrogenation, a second conjugate addition of tri-octylborane was used to introduce the w-chain (Scheme 25) [70]. 

In 2003, we reported a multicomponent approach toward highly substituted 2H-2-imidazolines (65) [157]. This 3CR is based on the reactivity of isocyano esters (1) toward imines as was studied in detail by Schollkopf in the 1970s [76]. In our reaction, an amine and an aldehyde were stirred for 2 h in the presence of a drying agent (preformation of imine). Subsequent addition of the a-acidic isocyanide 64 resulted in the formation of the corresponding 2//-2-imidazolines (65) after 18 h in moderate to excellent yield. The mechanism for this MCR probably involves a Mannich-type addition of a-deprotonated isocyanide to (protonated) imine (66) followed by a ring closure and a 1,2-proton shift of intermediate 68 (Fig. 21). However, a concerted cycloaddition of 66 and deprotonated 64 to produce 65 cannot be excluded. 

These a,/l-unsaturated ketones and aldehydes are used as reactants in Michael additions (Section 1.10) and Robinson annulations (Section 2.1.4), as well as in a number of other reactions that we will encounter later. Entries 8 and 9 in Scheme 2.11 illustrate Michael reactions carried out by in situ generation of a,/ -unsaturated carbonyl compounds from Mannich bases. 

Aminochromans also arise from the reaction of phenolic Mannich bases with enamines (70JHC1311). The route is attractive for a number of reasons the starting materials are readily available its scope is considerable since the enamines may be aldehyde or ketone based and the Mannich bases may be aromatic or heteroaromatic and the products themselves are precursors of hydroxychromans and 4//-chromenes. Mechanistically, the synthesis proceeds through a quinone methide followed by addition to the enamine and cyclization, which may be a concerted process (Scheme 71). 

The literally thousands of examples involving the addition of stabilized nucleophiles to activated alkenes and alkynes have spawned many reviews over the years. The Michael reaction has been discussed in detail several times7 and reviews on other related topics, such as annulation8 and Mannich base meth-iodides,9 have also appeared, as have several reviews on nucleophilic additions to activated alkynes.10... 

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). 

The elimination reaction can be followed only for pH > (pKvm — 2). The rate of the side reaction of the a,(i-unsaturated ketone increases with increasing pH and for phenylvinyl ketone becomes of importance at pH values above about 9. To study the elimination process unaffected by the hydration of the a,[3-unsaturated ketone generated, it was necessary to find a Mannich base the elimination of which would take place at pH << 9, i.e. with a.pKjtB 9. 3-Morpholinopropiophenone proved to be a suitable model (27) this compound has a pK B value of 6.8, so that constants ke and kaa at pH < 9 can be quantitatively evaluated without any effect from cleavage of the a,(3-unsaturated ketone. The validity of the kinetic equations corresponding to scheme (13) was proved both for the elimination of p-aminoketones (27) and for the addition of primary and secondary amines to a, (3-unsaturated ketones (28). 

A novel reaction that transfers chirality from an enantiopure tricarbonyl(dienal)iron complex in a Schiff base condensation reaction is followed by an intramolecular Mannich reaction to yield a piperidine which was then manipulated in additional five steps to dienomycin C 40 (Equation 109) <1999EJO 517>. 

Tfce preferred synthetic route to these important intermediates is the Mannich reaction (Chapter 27), The compound is stored as the stable Mannich base and the unstable enone released by elimination of a tertiary amine with mild base, The same conditions are right for this elimination and for conjugate addition, Thus the aw-methylene compounds can be formed in the flask for immediate reaction with the enol(ate) nucleophile, The overall reaction from (3-amino carbonyl to 1,5-dicarbonyl appears to be a substitution but the actual mechanism involves elimination and conjugate addition,... 

Either the tertiary amine or the quaternary ammonium salt can be stored as a stable equivalent of the exo-methylene compound. In our first example, the Mannich base with dimethylamine is first methylated with methyl iodide and then added to the conjugate addition reaction. Elimination of trimethylamine, which escapes from the refluxing ethanol as a gas, reveals the exo-methylene ketone in which the methylene group is exo to a chain. Fast conjugate addition of the stabilized enolate of diethyl malonate produces the product. 

In CHEC-II(1996) the detailed discussion of thiophenes as intermediates was, somewhat arbitrarily, limited to photochemical and electrocyclic processes. Additionally, reactions were included which destroy the aromatic thiophene skeleton to give rise to open chain molecules. In this scheme very recent applications of thiophenes such as thiophene-based amide linkers in solid-phase synthesis <2006JOC6734> or V-(2-thienyl)sulfonyl aldimins in chiral Mannich reactions <2006OL2977> did not be fit in. 

Diaslereoselective Mannich reaction. Mannich bases can be prepared by addition of a lithium dialkylamide to a nonenolizable aldehyde to form a lithium alkoxide. Trans-metallation provides a trichlorotitanium alkoxide, which reacts with a lithium enolate to form a Mannich base. 

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