Michael-type addition amines

Other reactions that show preference for the acidic N-3—H group include Mannich aminomethylation by treatment with formaldehyde and an amine (38) to yield compound (8), reaction with ethyleneimine (39) to give (9), and Michael-type additions (40) such as the one with acrylonitrile to give (10) ... 

This Michael-type addition is catalyzed by lanthanum(3+) [16096-89-2] (80). Ethylene glycol [107-21-1] reacts with maleate under similar conditions (81). A wide range of nucleophilic reagents add to the maleate and fumarate frameworks including alcohols, ammonia, amines, sulfinic acids, thioureas, Grignard reagents, Michael reagents, and alkali cyanides (25). 

In contrast, tertiary amines do not possess a proton to transfer, and the reaction of the Michael-type addition adduct with ECA can only initiate polymerization to form high molecular weight adhesive polymer, as shown earlier in Scheme 1. 

Scheme 5 Access to / -amino-substituted a,/ -unsaturated Fischer carbene complexes 30 by Michael-type addition of amines to alkynylcarbene complexes 23 (R=Et) [30,33]...

The history of dendrimer chemistry can be traced to the foundations laid down by Flory [34] over fifty years ago, particularly his studies concerning macro-molecular networks and branched polymers. More than two decades after Flory s initial groundwork (1978) Vogtle et al. [28] reported the synthesis and characterization of the first example of a cascade molecule. Michael-type addition of a primary amine to acrylonitrile (the linear monomer) afforded a tertiary amine with two arms. Subsequent reduction of the nitriles afforded a new diamine, which, upon repetition of this simple synthetic sequence, provided the desired tetraamine (1, Fig. 2) thus the advent of the iterative synthetic process and the construction of branched macromolecular architectures was at hand. Further growth of Vogtle s original dendrimer was impeded due to difficulties associated with nitrile reduction, which was later circumvented [35, 36]. This procedure eventually led to DSM s commercially available polypropylene imine) dendrimers. 

Michael-type addition of cyclic amines (piperidine, A-methylpiperazine) to thiazolo[3,2-A][l,2,4]triazole-5(6//)-ones 46 provides an easy entry to 2-aryl(alkyl)-6-(a-aminoarylmethyl)thiazolo[3,2- ][l,2,4]triazol-6(5//)-ones 207 (Equation 19) <1999AF1006, 2001AF470>. 

The importance of chiral thiols and thioether linkages in biological systems has prompted intense investigation of the use of chiral amines [see e.g. 5-11] and ammonium salts [see e.g. 12] as agents for asymmetric induction in the Michael-type addition reaction. Considerable success has been achieved using chinchona alkaloids and their A-alkyl derivatives (see Chapter 12). 

The diquinone 300 has been shown to react with a variety of primary amines producing carbazole quinones 301, a process which presumably involves an intermediate such as 302 formed by Michael-type addition. Alkyl-, aryl-, and heteroarylamines and amino acids have been utilized. The reaction failed with p-nitro- and p-acetylanilines neutral and acidic amino acids required base catalysis. Hydroxyl-... 

E/Z stereochemistry of a,/ -ethylenic phosphonium derivatives is essentially governed by steric factors apart from when there is extra stabilization, as is the case with betaines87. Z->E isomerization may be performed using sterically crowded amines (so that any Michael-type addition would be prevented)192,193. Spectrometry allows the progress of the reaction to be observed (Section I.C). 

The most common preparations of amines on insoluble supports include nucleophilic aliphatic and aromatic substitutions, Michael-type additions, and the reduction of imines, amides, nitro groups, and azides (Figure 10.1). Further methods include the addition of carbon nucleophiles to imines (e.g. the Mannich reaction) and oxidative degradation of carboxylic acids or amides. Linkers for primary, secondary, and tertiary amines are discussed in Sections 3.6, 3.7, and 3.8. 

A Michael-type addition of secondary amines or thiols to 3-methylene-2-oxetanones (33) and subsequent pyrolysis of the adduct (34, X = NR22 or SR2) to yield allylic amines (35, X = NR22) or sulphides (35, X = SR2) has been proposed as a useful alternative to the Wittig olefination procedure (95JOC578). 

Scheme 5.18 Michael-type addition of secondary amines to nitrothienyl-substituted alkynes.

Pyrrolidine Amines and Pyrrolidine Amine Salts as Catalysts for Michael-Type Addition of Ketones to Activated Olefins... 

Simple double aza-Michael reaction of divinyl ketones with primary amines was utilized to generate TV-substituted 3-phenyl-4-piperidones in good yields <07EJO4376>. In a somewhat similar mode, the diastereoselective synthesis of cyclic (3-amino esters by an Sn2 substitution-cyclization of an iodo-a,(3-unsaturated ester with (.Sj-u-mcthy 1 benzylamine was described <07OBC3614>. A combination intramolecular Michael-type addition followed by retro-Michael elimination was exploited in the generation of a phosphoryl dihydropyridone intermediate in the synthesis of /m .v-2,6-disubstitutcd 1,2,5,6-tetrahydropyridines <07JOC2046>. 

The regio- and enantioselectivity of the reactions depend on the structure of dipolarophiles and the addition of p-cyclodextrin. BY is also able to cany out a Diels-Alder condensation," and a few Michael-type additions are enantioselectively performed in the presence of BY. For example, the addition of amines to a,p-unsaturated esters affords optically active p-amino acid esters (eq 20). ... 

Asymmetric Michael Reactions. Asymmetric induction has been observed in Michael-type addition reactions that are catalyzed by chiral amines. The Ai-benzyl fluoride salt of quinine has been particularly successful since the fluoride ion serves as a base and the aminium ion as a source of chirality. Drastic improvements in optical purity (1-23%) have resulted by changing from quinine to the N-benzyl fluoride salt (eq 11). ... 

The homobifunctional cross-linker, glutaraldehyde (GA), can be used for conjugating the molecules containing primary amine groups with amine-terminated PMMA. This is where the formation of Schiff bases with possible rearrangement to a stable product or through a Michael-type addition reaction occurred. The reaction takes place at points of double-bind unsaturation created by polymerization of the GA in solution (121-122) (reaction shown in scheme 8.4). 

Most, a,jS-unsaturated esters other than methyl methacrylate undergo facile Michael type addition with primary and secondary amines to yield A -addition products. By carrying out the anthraquinone photosensitized addition of several secondary amines with a, -unsaturated esters at low temperatures ( 0°C), the thermal reactions could be controlled without adversely affecting the photochemical free radical reactions. Using this procedure, indolizidone, pyrrolizidone and a mixture of heliotridone and pseudoheliotridone was synthesized (Scheme 72) [326]. 

The Michael-type addition, a nucleophilic addition of an anion to the carbon-carbon double bond of an a,(3-unsaturated ketone, aldehyde, nitrile, nitro, sulphonyl, or carboxylic acid derivative, provides a powerful tool for carbon-carbon bond formation. The reaction is most successful with relatively nonbasic ( soft ) nucleophiles such as thiols, cyanide, primary and secondary amines, and P-dicarbonyl compounds. There is often a competition between direct attack on the carbonyl carbon (1,2-addition) and conjugate addition (1,4-addition) when the substrate is an a,(3-unsaturated carbonyl compound. 

The maleimide group can undergo a variety of chemical reactions, including polymerizations induced by free radicals or anions. Nucleophiles such as primary and secondary amines , as well as thiophenoxides , can react via a classical Michael-type addition mechanism . The maleimide group can also act as a very reactive dienophile and is thns nsed in a variety of Diels-Alder reactions . By varying the natnre of the linkages between the maleimide rings, the physical properties of the bis(maleimide) can be altered. 

A mechanism for the formation exo-5-morpholinobicyclo[2.2.1]heptan-2-one via a ho-moenolate ion intermediate in a Michael-type addition reaction has been proposed. Michael addition reactions involving secondary amines and a,)S-unsaturated carbonyl compounds have been reported, but this was the first example of such a reaction involving the ho-moenolate ion. ... 

They speculated that the imidazolium cation of [pmim][Br] activates CS toward nucleophilic attack by amine to generate a dithiocarbamate anion, which can then undergo Michael-type addition to conjugated alkenes to afford the substituted dithiocarbamate (Fig. 12.59). 

To investigate further modifications of the resin-bound allylic alcohols, we synthesized 1,3-amino alcohols via a non stereoselective Michael-type addition of amines (Fig. 6.5). 

Like most other aspects of the luzopeptin effort, deblocking of hard-won dipeptides 106 and 107 turned out to be a delicate proposition. In derivatives of proline and pipecolinic acid, the serine segment had been extricated from its protective webbing by A-deacetylation with pyrrolidine in aeetonitrile and Kunieda cleavage of the oxazolone. However, reaction of 106 with pyrrolidine furnished 109 (30%) as the sole identifiable compound. Evidently, pyrrolidine was basic enough to promote p-elimination of acetate and subsequent Michael-type addition to intermediate 108, a significant fraction of which may have been lost to polymerization. Other amines, such as ethylamine, diethylamine. 

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