The Conjugate Addition of an Amine

The conjugate addition of an amine to an a,p-unsaturated carbonyl com-pound/nitrile has been achieved in water without any catalyst at room temperature (Scheme 5.15). The rate acceleration of the reaction was explained by H-bonding of H2O to the amine and carbonyl group of alkene. 

The Aldol Cyclization 877 The Conjugate Addition of HCN 879 The Conjugate Addition of an Amine 879 The Michael Addition 880 The Mannich Reaction 882... 

However, the presence of an alkene exo to the chain 40 stops the reaction, presumably because the 120° angle holds the ends too far apart. The solution is conjugate addition of an amine 41 the acyloin then works well 42 and the synthesis of the flavouring compound corylone 43 is completed simply by a silica column.7 Hydrolysis of the silyl enol ethers leads to elimination of Me2NH under the slightly acidic conditions. 

The [3-amino carbonyl product of conjugate addition of an amine is still an amine and, provided it has a primary or secondary amino group, it can do a second conjugate addition. For example, methylamine adds successively to two molecules of this unsaturated ester. 

In this series of reactions, conjugate addition of an amine to an a,(3-unsaturated ester is followed by nucleophilic addition of the amine to a second ester, with loss of methanol. 

The procedure given here stems from our synthetic effort toward (+)-jasplakinolide9 11 that contains the p-amino acid (R)-p-tyrosine.12 This protocol permits the introduction of the desired carbon substituted at the p-site in an enantioselective manner. This approach contrasts with previous methodologies, which develop the chiral center via conjugate addition of an amine to an a,p-unsaturated system,13 reduction of a C=C or C=N functionality,14 or C-C bond formation involving imines and enolate derivatives.15... 

Conjugate addition. The catalyzed addition of an amine to an unsaturated ester to afford a 8-amino ester (precursor of /3-lactam) is subject to stereocontrol by the environment at the y-carbon atom of the ester. High pressure has a favorable effect on reactions of hindered reactants. ... 

The lithium trialkylzinc reagents LiZnR3 prepared from RLi and zinc(ll) chloride effect the conjugate addition of an alkyl group (R) to a/8-unsaturated ketones. The acid-catalysed addition of some secondary amines to monoactivated cyclopropyl ketones has been examined. ... 

The conjugate addition of a carbon nucleophile to an a./3-unsiituratcd acceptor is known as the Michael reaction. The best Michael reactions take place between unusually acidic donors (/3-keto esters or /3-diketones) and unhindered n,/3-unsaturated acceptors. Knamines, prepared by reaction of a ketone with a disu Instituted amine, are also good Michael donors. 

Other nucleophiles add to conjugated systems to give Michael-type products. Aniline derivatives add to conjugated aldehydes in the presence of a catalytic amount of DBU (p. 488). Amines add to conjugated esters in the presence of InCla, La(OTf)3, or YTb(OTf)3 at 3kbar, for example, to give P-amino esters. This reaction can be initiated photochemically. An intramolecular addition of an amine unit to a conjugated ketone in the presence of a palladium catalyst, or... 

Planar surfaces activated with the NHS-PEG groups may be sealed in a pouch and stored dry in the presence of a desiccant. Activated particles may be stored as a suspension in dry solvent under a head of nitrogen at 4°C until used for further conjugation. The addition of an amine-containing protein or other amine-molecule will cause covalent coupling to the surface NHS ester groups to form amide bonds. 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

In a series of reports between 1991 and 1997 Yamaguchi showed that rubidium salts of L-proline (9) catalysed the conjugate addition of both nitroalkanes [29, 30] andmalonates [31-33] to prochiral a,p-unsaturated carbonyl compounds in up to 88% ee (Scheme 1). Rationalisation of the selectivities observed involved initial formation of an iminium ion between the secondary amine of the catalyst and the a,p-unsaturated carbonyl substrate. Subsequent deprotonation of the nucleophile by the carboxylate and selective delivery using ion pair... 

If the chemistry is amenable, it is possible to synthesize a large number of small samples of polymers by simply mixing the ingredients in either small vials or multiwell plates. For example, Brocchini et al. prepared a library of 112 polymers by mixing the monomers in individual vials which were placed in a water bath [22]. Akinc et al. synthesized a library of 24 unique poly(j3-amino esters) via the conjugate addition of acrylates and amines by mixing the monomers in sample vials fitted with stir bars [23]. To speed up this process, a liquid handling robot can be used to dispense the raw materials into an array of vials [24]. 

While sluggish under thermal conditions,274-275 the asymmetric conjugate addition of amines to alkyl crotonates is achieved at room temperature under high pressure (15 kbar).276 Thus, benzylamine can be added to the crotonate derived from 8-p-naphthyl menthol, with virtually complete diastereoselectivity. A related intramolecular 1,4-addition of an amine to a chiral enoate was used in a total synthesis of the alkaloid (-)-tylophorine.277 Additions of amines to chiral iron complexes of type (116) proceed with excellent selectivity and allow the preparation of homochiral p-lactams.l27128,l3() l32 In contrast, the addition of amine nucleophiles to chiral vinylic sulfoxides278-2811 and to chiral vinylsulfoximines281 proceeds with comparably low selectivities. 

The Michael reaction is the conjugate addition of a soft enolate, commonly derived from a P-dicarbonyl compound 24, to an acceptor-activated alkene such as enone 41a, resulting in a 1,5-dioxo constituted product 42 (Scheme 8.14) [52]. Traditionally, these reactions are catalyzed by Bronsted bases such as tertiary amines and alkali metal alkoxides and hydroxides. However, the strongly basic conditions are often a limiting factor since they can cause undesirable side- and subsequent reactions, such as aldol cyclizations and retro-Claisen-type decompositions. To address this issue, acid- [53] and metal-catalyzed [54] Michael reactions have been developed in order to carry out the reactions under milder conditions. 

We end this chapter with a simple commercial synthesis of a drug molecule described as a dopaminergic antagonist. It uses four reactions that you have met conjugate addition of an enolate to acrylonitrile reduction of CN to a primary amine alkylation and reduction of the amide. There is another reaction involved—cyclization to an amide—but this occurs spontaneously. These reactions may be simple but they are important. 

Mechanistically, two scenarios have been advanced. The first involves coordination of the nitrile to the Ru center which is followed by nucleophilic attack at the nitrile, while the second entails a sequence of events starting with oxidative addition of water, an alcohol or an amine to the metal center, followed by insertion of the nitrile into the Ru-OH bond. A recent report describes the conjugate addition of alcohols to acrylonitrile compounds catalyzed by a mthenium-acetamido complex [Ru(PCy3)2(CO)(CH3CONH)-(i-PrOH)H] (7) (Scheme 10.13) [17]. The mechanistic investigation of this reaction supports the proposal that the N-coordination of acrylo-... 

---