Catalyzed by Secondary Amines

1 Catalyzed by Secondary Amines Substhuted with Bulky Croups 

Mechanism After the first report of iminium activation by MacMillan et al. in 2000, many studies have been made in this area. Two of the most important famihes of catalysts are MacMillan s catalysts and the TMS O-protected diaryl substituted prolinols developed independently by Jorgensen and Hayashi in 2005. 

2 Catalyzed by Secondary Amines Substituted with Hydrogen-Bond-Directing Croups 

Mechanism Secondary amines bearing hydrogen-bond directing groups have often been used in the activation of cyclic enones. The commonly accepted 

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Aldol-type reactions of nitrones (303) occur with electron-deficient ketones, such as a-keto esters, a, 3-diketones, and trifluoromethyl ketones. These reactions are catalyzed by secondary amines. The use of chiral cyclic amines A1-A7 leads to a-(2-hydroxyalkyl)nitrones (304) in moderate yields and rather high optical purity (Scheme 2.120) (381). The mechanism of the nitrone-aldol reaction of iV-methyl-C-ethyl nitrone with dimethyl ketomalonate in the absence and presence of L- proline has been studied by using density functional theory (DFT) (544). 

In the reaction of 1-naphthol with 3-nitro-4-fluorobenzalmalononitrile in ethanol, catalyzed by secondary amines, nucleophilic displacement of fluorine competes with pyran ring closure. Application of a tertiary amine (N-methylmorpholine) leads to the selective formation of the corresponding aminochromene (94H(38)399). 2,3-, 1,8-Dihydrooxynaphthalenes 148 and 149 react with 1 or 2 equiv. of aromatic aldehyde 28 and MN 27a to yield naphthopyrans 150 and 151 or dipyrans 152 and 153 (90IJB885, 02RCB2238) (Scheme 53). 

The same group reported the striking observation that oxygen transfer from ox-one to substrate olefins can also be catalyzed by secondary amines alone [49]. Pyrrolidines proved particularly efficient in this process, which was originally believed to involve the amine radical cation. Subsequent work [50, 51] identified the proto-nated amine as the active species and assigned a dual role to it. It is most probable that the ammonium cation acts both as a phase-transfer catalyst and forms a com-... 

As stated above, the studies of Wieland and Miescher, as well as Woodward, on the intramolecular aldol reaction of diketones and dialdehydes were encouraged by this previous work. Wieland, Miescher, and Woodward studied the application of the intramolecular aldol reaction, catalyzed by secondary amine salts, to the synthesis of steroids and believed that their aldolizations proceed via enamine intermediates [ 10]. This was corroborated by the mechanistic studies carried out by Spencer in 1965 [11]. Based on these works, Hajos and Parrish (1974) andEder, Sauer, and Wiechert... 

A different approach was reported by Enders in 2008 et al. [35]. In this work aldehydes react with halo-nitroalkenes (44) via a Michael-alpha alkylation reaction catalyzed by secondary amines, affording the final cyclopentanes in good yields and excellent enantioselectivities (Scheme 10.15). 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

Variably substituted 2-aminothiophenes 260,262, and 264 have been synthesized by several groups in the last years by the application of modified Gewald reactions (Scheme 13.61). Those reactions were catalyzed by secondary amines like piperidine [99] andproline [100] andbypolysiloxane-bound primary amines [101]. In the first case, an equimolar amount of piperidine has been used in the last two cases, only catalytic amounts of the amines were necessary. All reactions were conducted iu polar solvents at elevated temperatures and the desired products could be isolated in moderate to high yields. 

Scheme 2.25 Mechanism for the catalytic enantioselective a-heteroatom functionalization of aldehydes and ketones catalyzed by secondary chiral amines.

A-methylation is an important reaction by which primary, secondary, and tertiary amines are substrates of methylation. Most tissues catalyze the methylation of a large variety of amines. The source of the methyl group that is transferred in each instance is SAM, and the products are secondary, tertiary or quaternary N-methylamines as well as. S -adenosyl-L-homocysteine (SAH). The reaction shown below is with a primary amine as substrate and is catalyzed by an amine N- m e I h y I transferas e. 

The term aminocatalysis has been coined [4] to designate reactions catalyzed by secondary and primary amines, taking place via enamine and iminium ion intermediates. The field of asymmetric aminocatalysis, initiated both by Hajos and Parrish [5] and by Eder, Sauer, and Wiechert [6] in 1971, has experienced a tremendous renaissance in the past decade [7], triggered by the simultaneous discovery of proline-catalyzed intermolecular aldol [8] and Mannich [9] reactions and of asymmetric Diels-Alder reactions catalyzed by chiral imidazolidinones [10]. Asymmetric enamine and iminium catalysis have been influential in creating the field of asymmetric organocatalysis [11], and probably for this reason aminocatalytic processes have been the object of the majority of mechanistic smdies in organocatalysis. 

In 2010 Kotsuki [24] reported high-pressure studies on a difficult Diels-Alder reaction of furan and acrolein catalyzed by secondary and primary amines, for example, proline, phenylalanine, diphenylprolinol, and the MacMillan catalyst (Scheme 21.6). The best results in terms of yield were obtained with simple amino acids (proline and phenylalanine) under 8kbar but, unfortunately, were accompanied with very low ee. The use of lower pressure (2kbar) and prohne as a catalyst resulted in very low yield and an increase in enantioselectivily up to 21%. 

Based on the above-mentioned stereochemistry of the allylation reactions, nucleophiles have been classified into Nu (overall retention group) and Nu (overall inversion group) by the following experiments with the cyclic exo- and ent/n-acetales 12 and 13[25], No Pd-catalyzed reaction takes place with the exo-allylic acetate 12, because attack of Pd(0) from the rear side to form Tr-allyl-palladium is sterically difficult. On the other hand, smooth 7r-allylpalladium complex formation should take place with the endo-sWyWc acetate 13. The Nu -type nucleophiles must attack the 7r-allylic ligand from the endo side 14, namely tram to the exo-oriented Pd, but this is difficult. On the other hand, the attack of the Nu -type nucleophiles is directed to the Pd. and subsequent reductive elimination affords the exo products 15. Thus the allylation reaction of 13 takes place with the Nu nucleophiles (PhZnCl, formate, indenide anion) and no reaction with Nu nucleophiles (malonate. secondary amines, LiP(S)Ph2, cyclopentadienide anion). 

Other secondary amines such as pyrrolidine, di- -butylamine, tetrahydro-quinoline, n-benzylamine, and piperidine were also found to be capable of effecting this reduction. Interestingly, morpholine does not reduce enamines as readily (47) and its acid-catalyzed reaction with norbornanone was reported (45) to give only the corresponding enamine (93), although trace amounts of the reduction product were detected when cyclohexanone was treated with morpholine under these conditions (47a). The yield of morpholine reduction product was increased by using higher temperatures. 

The -butylformamidine was used to protect and direct the course of metalation of secondary amines. It is formed from A, A-dimethyl-A -r-butylformamidine by an acid-catalyzed exchange reaction or from the A-r-butylimidate tetrafluorobo-rate salt and is cleaved with hydrazine. 

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