Michael Addition of Amines

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). 

Finally, the scope and limitations of this solid-phase approach were investigated by varying aldehydes (Table 6.1) and amines (Table 6.2).The compounds were all characterized using ES-MS and analytical HPLC. 

Prien et al. [18] used secondary amines for the formation of 1,3-amino alcohols. Another substituent was introduced by aminolytic cleavage under the formation of C(2), C(3)-disubstituted 3-hydroxypropionic acid amides. Thirty-six compounds were synthesized, with yields ranging from 40 % to 66 % (Fig. 6.6). 

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In the synthesis of N heterocycles, this technique also overcomes competitive retro Michael addition that lowers the yield of 1,4-adduct in the Michael addition of amines to nitro olefins. Thus, a toluene solution of nitro olefin 159 was treated with allylamine 160, EtgN, and TMSCI under nitrogen at ambient tern-... 

Scheme 5.20 Lipase-catalyzed Michael addition of amines to acrylonitrile.

In a similar way, lipases catalyze Michael addition of amines, thiols [110], and even 1,3-dicarbonyl derivatives [111, 112] to a,/ -unsaturated carbonyl compounds (Scheme 5.21). 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Another approach for the synthesis of networks relies on the polycondensation of multifunctionalized polyesters with the appropriate multifunctionalized agent, provided that one of the partner is at least tri-functionalized. Toward this end, several reaction have been reported, such as the Michael addition of amines onto acrylates [184], the coupling of ketones and oxyamines [185], the click copper(II)-catalyzed azide-alkyne cycloaddition [186], and esterification reactions [25, 159, 187]. Interestingly, if esterification reactions are used, the crosslinks are then degradable. 

Michael addition of amines to bis(acrylamides) has provided a versatile method for the preparation of poly(amidoamines) (70MH1102). A wide variety of piperazine-containing polyamides may be prepared by this route when a piperazine, 1,4-diacryloylpiperazine... 

Okumoto, S., Yamabe, S. A theoretical study of curing reactions of maleimide resins through Michael additions of amines. J. Org. Chem. 2000, 65, 1544-1548. 

Schreiner, E. P. Pruckner, A., Syrc-Selective Michael Addition of Amines to Bis-Enones Synthesis of 1,3,4,7-Tetrasubstituted (4R, 5S, 6S, 7R)-Hexahydro-5,6-dihydroxy-2H-l,3-diazepin-2-ones J. Org. Chem. 1997, 62,5380. 

Under thermal activation conditions, ester 161 reacts with benzylamine to give a mixture of a-amino-p,y-unsaturated ester 164 and amide 165, but under 1.1 GPa pressure ester 161 gives the spiro-aziridines 162 and 163 in high yield and good diastereoselectivity. These are part of an attractive class of compounds that are formed by hetero-Michael addition of amine onto the unsaturated ester 161, followed by intramolecular nucleophilic substitution of the bromine atom (Scheme 7.41). ... 

Due to the presence of two functional groups, there is a wide range of possible postmodifications. One possibility is the conversion of the double bond, as in the Michael addition of amines leading to 1,3-amino-alcohols [19], by epoxidation or a Michael addition of a P-ketoester to form pyrazolones [23] after the conversion into hydrazones, followed by an intramolecular cyclization. 

Amino-acids. - A classical route to 3-amino-acids is by Michael additions of amines to a,8-unsaturated esters. Such reactions can be accelerated by the application of high pressure and performed... 

The same complex in triethylamine causes dehydration of the )8-amino ketones 39 to the enaminones 40 in excellent yields. Scheme 12. This method is useful because the /3-amino ketones are readily available from Mannich reactions or from Michael additions of amines to enones (84CL-1419 87BCJ3285),... 

Thus, as depicted in Scheme 4.4.11, starting from acrylic acid substituted resin 291, polymer-bound pyrrolidinones 292 were easily prepared by sequential Michael addition of amines followed by cyclisation with diethyloxalate. After substitution reaction with different 3-aminopyrazoles at 100°C, subsequent treattnent with 5N HCl at 80°C afforded with concomitant cleavage from the resin, the corresponding pyrazolopyrrolopyrimidinediones 294. Additional molecular diversity could be introduced by alkylation of the liberated compounds 294 in solution to give 295. 

The Michael addition of amines to a,p-unsaturated thioamides has been carried out [43]. The reaction of tertiary a,p-unsaturated thioamides 59 with cyclic amines such as pyrrolidine, morpholine, and piperidine proceeds slowly (Eq. 19). After five days, the adducts 60 are obtained as stable compounds in moderate yields. On the other hand, the products derived from the addition of pyrrolidine to secondary a,p-unsaturated thioamides 61 are unstable. The stereochemistry of the Michael addition to cyclic a,p-unsaturated thioamides 62 is dependent on the substituents on the nitrogen atom. 

The low melting and liquid halide salts in Table 1 have found utility as ILs. McNulty et al. have reported high yields for palladium cross-coupling reactions using entry 9 (CYPHOS ILlOl) as a recyclable solvent/catalyst system [15], Similarly, Kaufmann et al. have reported that entry 12 can be used repeatedly with the same palladium catalyst to obtain high conversions of Heck coupling products [16]. Ramani has demonstrated that entry 9 can be successfully employed for a variety of reactions such as quantitative Michael addition of amines to acrylate esters [17], palladium-catalyzed carbonylation of iodobenzene to obtain ethyl benzoate [9], and Heck coupling of iodobenzene and ethyl acrylate [19]. 

K. Surendra, N. Srilakshni, R. Sridhar, K. R. Rao, j8-Cyclodextrin promoted aza-Michael addition of amines to conjugated aUcenes in water. Tetrahedron Lett., 2006, 47, 2125-2127. 

Michael addition of thiols across the 10,11-double bond has occurred in tylosin derivatives in which the aldehyde had been protected as its dithioketal [134, 139] a comment about successful Michael additions of amines was also... 

The investigation of catalyst-free mechanochemical aza-Michael addition of amines with chalcones by Li et al. led to the formulation of an efficient synthetic protocol (Scheme 3.74) [49]. By applying optimal reaction conditions, a number of aliphatic and aromatic amines 278 in equimolar ratio were reacted with chalcones 277 to obtain azo-Michael products 279 in 44-99% yields (Table 3.37). Compared with conventional methods, the main advantages of the mechanochemical procedure are milder conditions, higher yield, shorter reaction time, and occurrence of no side reactions. 

Table 3.37 Aza-Michael Addition of Amines to Chalcones —cont d...

Amines or sulfides by Michael addition of amines or thiols to vinyl groups... 

Working in the area of elastomers, Itovaclc (U. S. Patent 2,818,407 Dec. 31, 1957) reported the Michael addition of amine capped prepolymers to bls-maleimides. Similarly, Sheremeteva euid co-workers found that reaction of stoichiometric amounts of bls-maleimides and primary aromatic diamines in refluxing ethanol afforded polymers, vAiich thermally degraded so rapidly that they could not be considered heat resistant. 

Firouzabadi, H., Iranpoor, N., Jafarpour, M. and Ghaderi, A. 2006a. Zr0Cl2-8H20 as a highly efficient and the moisture tolerant Lewis acid catalyst for Michael addition of amines and indoles to a, 3-unsaturated ketones under solvent-free conditions. J. Mol. Catal. A Chem. 252 150-155. 

Pore et al. (2006) documented the thia-Michael addition involving the conjugate addition of thiols to a,p-unsaturated ketones in the presence of SSA as a heterogeneous catalyst under solvent-free conditions at room temperature (Scheme 5.53). The catalytic activity was comparatively studied with potassium phosphate. Studies revealed that SSA is suitable for electron-deficient a,P-unsaturated compounds, whereas K3PO4 catalyzed the reactions of both electron-deficient as well as electron-rich enones. SSA catalyzes a rapid, green, and chemoselective aza-Michael addition of amines and thiols... 

Other examples of Michael additions are the reaction of nitroolefins with acetone on L-proline-modified Mg-Al mixed oxides (51) or with diethyl malonate on metalorganic MCM-41 (52), or the addition of nitromethane to unsaturated carbonyl compounds on KF-modified alumina (53). Furthermore, solid catalysts such as montmorillonite clays and hydroxyapatite have recently been employed for the construction of S—C bonds by /lia-Michael addition of thiols to unsaturated ketones and other carbonyl compounds (54,55). Similarly, aza-Michael additions of amines to alkenes activated by -CN, -COOR, or -COR groups, lead to C—N bond containing products on Amberlyst-15 or polyaniline supported Cul (56,57). 

Synthesis.—Mannich-type Reactions. The double Michael addition of amines to cyclohepta-2,6-dienone has been extended by the use of a series of optically active primary amines to the synthesis of chiral 8-azabicyclo-[3,2,l]octanes. Yields are typically ca. 70% circular dichroism studies show interesting effects. Perturbation of the n - rr transition must originate in the asymmetry of the nitrogen substituents which lie in the symmetry plane of the ring. The analysis of the tertiary amines is complicated by... 

RTE.S and their polymeric derivatives are convenient green catalysts and recyclable for acetylation of various transformations of alcohols, phenols, amines, thiols to o,p-unsaturated esters and aciylonitrile and Michael additions of amines. 

Several transition metal-based Lewis acid catalysts such as FeCls, CrCls, SnCU, or A1(03S0Ci2H25 )s were shown to be highly effective for aza-type Michael additions of amines such as indoles and pyrroles to a,/ -unsaturated compounds in aqueous solution. Addition of thiols to a,/ -unsaturated ketones in water was also catalyzed by SDS or /3-cyclodextrin. There is also a single report on the stereoselectivity of base-catalyzed Michael additions of thiols to nitro-olefins, where moderate diastereoselectivities were obtained (Scheme 8.13). 

Firouzabadi, H., Iranpoor, N. and Jafari, A. A., Micellar solution of sodium dodecyl sulfonate (SDS) catalyzes facile Michael addition of amines and thiols to a, -unsaturated ketones in water under neutral conditions, Adv. Synth. Catal., 2005, 347, 655-661. 

Naidu, B.N., Sorenson, M.E., Connolly, T.P. and Ueda, Y, Michael addition of amines and thiols to dehydroalanine amides a remarkable rate acceleration in water, /. Org. Chem., 2003,68, 10098-10102. 

Xu, L.-W., Li, L. and Xia, C. G., Transition-metal-based Lewis acid catalysis of aza-type Michael additions of amines to a,/ -unsaturated electrophiles in water, Helv. Chim. Acta, 2004, 87,1522-1526. 

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