Amines Michael-type reactions

Not only alkylations, but also Michael-type reactions, with weakly basic heterocyclic amines, can be accomplished by PTC. Yamada and Ohki158 have recently reported such a reaction with pyridazinones (99). 

Enamines, the products of the acid-catalyzed addition of secondary amines to aldehydes or ketones, can be viewed as weakly nudeophihc enolate anions. Enamines react with a,p-unsaturated carbonyl systems in a Michael-type reaction, introducing new carbon-carbon bonds adjacent to the carbonyl group. Endocyclic enamines, such as pyrroHnes and tetrahydropyridines, are useful for the synthesis of complex heterocycHc compounds, as found in many alkaloids (Scheme 3.19). 

Reactions with Nucleophiles. As an enone tropone is readily susceptible to attack by nucleophiles in Michael-type reactions which might take place at any site in the ring. An early reported example was the formation of 2-aminotropone by reaction with either hydrazine or hydroxyl amine [169]. Reaction olsviously proceeds by conjugate attack (preferred over attack at the carbonyl group) followed by elimination of water or ammonia ... 

A significant number of reports have appeared in the literature on the uses of maleimide or polymaleimide additives to obtain polymers with increased thermal and mechanical properties. For example, various rubbers with residual unsaturation have been effectively vulcanized with these additives. Though the maleimides can be cured via an amine Michael-type addition reaction (1) or with certain alkali metal salts (2), the most common method appears to be thermal polymerization with or without the use of peroxide initiator (3,4). 

Key contributions in the development of late transition metal catalysts toward alkene hydroamination, which precede the 2008 comprehensive review [10], focus on contributions using group 9 and 10 metals. Preferred substrates for these transformations include aminoalkenes [230] for intramolecular reactivity or the use of activated alkenes such as styrene [93, 109, 113, 245] or alkenes substituted with electron-withdrawing substituents to generate hydroamination products via aza-Michael-type reactions [246-249]. Au has also been applied to the hydrofunctionalization of alkenes, although these reactions have demanded the use of protected amine substrates such as ureas [250], tosylamides [251], and carbamates [252]. 

The simple chiral secondary amine (S)-70 activates the linear aldehyde 139 by enamine formation, which selectively attacks the nitroalkenes 140 in a Michael-type reaction without any interference by the a,p-unsaturated aldehyde 95. Indeed, the latter prefers to be activated as iminium ion by the catalyst (5)-70 and to undergo the subsequent conjugate addition to form the Michael adduct B (Scheme 2.41). 

Mechanism of action. Acrolein has two functional groups that can contribute to its biocidal activity. It is an a, jS-unsaturated aldehyde and as such the carbon-carbon double bond is extremely reactive. Nucleophiles, typically sulfur based nucleophiles, can react with the terminal carbon in a Michael type reaction (March, 1992), while the aldehyde group can undergo reactions typical of all aldehydes. From a biocidal point of view, those sulfur-based nucleophiles would include cysteine residues of the cell wall and those proteins associated with the cell wall. The amine containing amino acids (lysine and arginine) may also react with the aldehyde group of acrolein. 

In the present paper we wish to report on the most significant examples of chiral polymer-supported onium salts and polymeric amines which have been used in heterophase reactions. In the first part attention will be paid to describe the Michael-type reactions that have been rather extensively studied by several research groups. Even though they constitute an example of application placed right at the borderline of base catalyzed reactions performed under conventional and phase transfer conditions, they appear worthy of comment by virtue of the achieved valuable and reproducible optical yields in the chemical transformation of several prochiral substrates. 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

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) ... 

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. 

Surprisingly, the 7t-system geometry in a substrate has a notable influence in the enzymatic aminolysis of esters. The reaction of diethyl fumarate with different amines or ammonia in the presence of CALB led to the corresponding trans-amidoesters with good isolated yields, but in the absence of enzyme, a high percentage of the corresponding Michael adduct is obtained (Scheme 7.9). Enzymatic aminolysis of diethyl maleate led to the recovery of the same a, P-unsaturated amidoester, diethyl fumarate, and diethyl maleate. The explanation of these results can be rationalized via a previous Michael/retro-Michael type isomerization of diethyl maleate to fumarate, before the enzymatic reaction takes place. In conclusion, diethylmaleate is not an adequate substrate for this enzymatic aminolysis reaction [23]. 

Other nitrogen compounds, among them hydroxylamine, hydrazines, and amides (15-9), also add to alkenes. Even with amines, basic catalysts are sometimes used, so that RNH or R2N is the actual nucleophile. Tertiary amines (except those that are too bulky) add to Michael-type substrates in a reaction that is catalyzed by acids like HCl or HNO3 to give the corresponding quaternary ammonium salts. " ... 

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... 

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 majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

By 1989 Mukaiyama had already explored the behaviour of phosphonium salts as Lewis acid catalysts. It was possible to show that the aldol-type reaction of aldehydes or acetals with several nucleophiles and the Michael reaction of a,j3-unsatu-rated ketones or acetals with silyl nucleophiles gave the products in good yields with a phosphonium salt catalyst [116]. In addition, the same group applied bisphosphonium salts as shown in Scheme 45 in the synthesis of ]3-aminoesters [117]. High yields up to 98% were obtained in the reaction of A-benzylideneaniline and the ketene silyl acetal of methyl isobutyrate. Various analogues of the reaction parteers gave similar results. The bisphosphonium salt was found to be superior to Lewis acids like TiCl and SnCl, which are deactivated by the resulting amines. 

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. 

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