Mannich type reaction

The Mannich type reaction was also used for the synthesis of P-amino 

The Mannich and related reactions provide one of the most fundamental and useful methods for the synthesis of /3-amino ketones. Although the classical protocols include some severe side reactions, new modifications using preformed iminium salts and imines have been developed [18]. These materials however, are often hy- 

The present method provides a useful route for the synthesis of p-amino ketones. 

A possible mechanism of the present reaction is accompanied by imine formation, and successive addition of a vinyl ether proceeds smoothly in aqueous solution. Use of lanthanide triflates, water-tolerant Lewis acids, is of key importance and essential in this reaction. 

The chiral-modified binaphthol complex (23) has been prepared (Eq. 10) and shown to be an efficient catalyst for enantioselective Memnich-type reactions [9]. The reaction of imine (24) with ketene silyl acetal in the presence of the catalyst 23 with NMI afforded /3-amino acid derivatives 25 and 26 in high enantioselectivity (Eq. 11). 

The classic direct Mannich reaction, discovered in 1912, is an aminoalkyla-tion of carbonyl compounds involving ammonia (or a primary or secondary amine derivative), a non-enolisable aldehyde (usually formaldehyde) or a ketone, and an enolisable carbonyl compound, leading to p-amino carbonyl derivatives. Catalytie asymmetric Mannich-type reactions of aldehydes, ketones, esters, and other donors for the synthesis of p-amino carbonyl 

Mannich-type reaction of a,p-unsaturated ybutyrolactams with JV-Boc-imines in the presence of a preformed dinuclear nickel catalyst derived from a Schiff hase ligand. 

In conclusion, an important amount of work has been done in the last 10 years to develop asymmetric control in the aldol- and Mannich-type reactions catalysed by chiral nickel complexes. This catalysis is intrinsically elegant and economical, but it appears that, at least for the time being, it is still limited to simpler substrates in most cases. In addition, further studies will have to focus on better understanding asymmetric control in these reactions. 

With a Pd-catalyst I. Fukuchi, Y. Hamashima and M. Sodeoka, Adv. Synth. Catal, 2007, 349, 509-512, with a Rh-catalyst R. Kuwano, H. Miyazaki and Y. Ito,/ Organomet. Chem., 2000, 603,18-29. 

Matsunaga and M. Shibasaki, Chem. Commun., 2009,5138-5140. 

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In a second attempt to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, we have used the Mannich reaction to convert a ketone-activated monodentate dienophile into a potentially chelating p-amino ketone. The Mannich reaction seemed ideally suited for the purpose of introducing a second coordination site on a temporary basis. This reaction adds a strongly Lewis-basic amino functionality on a position p to the ketone. Moreover, the Mannich reaction is usually a reversible process, which should allow removal of the auxiliary after the reaction. Furthermore, the reaction is compatible with the use of an aqueous medium. Some Mannich reactions have even been reported to benefit from the use of water ". Finally, Lewis-acid catalysis of Mannich-type reactions in mixtures of organic solvents and water has been reported ". Hence, if both addition of the auxiliary and the subsequent Diels-Alder reaction benefit from Lewis-acid catalysis, the possibility arises of merging these steps into a one-pot procedure. 

Mannich-Type Reactions. Secondary nitroparaffins, formaldehyde (qv), and primary or secondary amines can react ia one step to yield Mannich bases. 

Tetrahydro-y-carbolines may be prepared by an internal Mannich-type reaction between 2-j8-aminoethyhndoles and formaldehyde. Kebrle et al. prepared 27 by the reaction of 2-lithio-l-methyl-indole with A-benzyl-A-ethylaminoacetone followed by debenzyl-ation treatment of 27 with formaldehyde led to the formation of the tetrahydro-y-carboline 28. Similarly, when the quaternary salts (30) of the Mannich bases (29) are heated at 100°, 1,2,3,4-tetrahydro-y-carbohnium salts (31) are formed. 

The assumed transition state for this reaction is shown in Scheme 5.5. The two bulky t-butoxy groups are expected to locate at the two apical positions. One of the 3,3 -phenyl groups would effectively shield one face of an imine, and consequently, a diene attacks from the opposite side. Judging from this model, similar selectivities were expected in the Mannich-type reactions of imines with silyl eno-lates. Actually, when ligand 10 was used in the reaction of imine la with S-ethyl-thio-l-trimethylsiloxyethene, the corresponding / -amino thioester was obtained in 84% ee (Scheme 5.6). As expected, the sense of the chiral induction in this case was the reverse of that observed when using catalyst 6 [12, 25]. 

Macrolides, synthesis of 632 Mannich-type reactions 641 Mass spectrometry... 

Since a small amount of water is always present in novolac resins, it has also been suggested that some decomposition of HMTA proceeds by hydrolysis, leading to the elimination of formaldehyde and amino-methylol compounds (Fig. 7.15).42 Phenols can react with the formaldehyde elimination product to extend the novolac chain or form methylene-bridged crosslinks. Alternatively, phenol can react with amino-methylol intermediates in combination with formaldehyde to produce ortho-or para-hydroxybenzylamines (i.e., Mannich-type reactions). 

Ph (SbFe)2 Ph Ph TIO OTf Ph 84 Scheme 14 Catalytic asymmetric aza-Henry (nitro-Mannich-type) reactions... 

In the first step, catalyst 64c attacks ketene 66 to form a zwitterionic enolate 71, followed by Mannich-type reaction with imine 76 (Fig. 40). A subsequent intramolecular acylation expels the catalyst under formation of the four-membered ring. Utilizing 10 mol% of 64c, N-Ts substituted (3-lactams 77 were prepared from symmetrically as well as unsymmetrically substituted ketenes 66, mainly, but not exclusively, with nonenolizable imines 76 as reaction partners [96]. Diastereos-electivities ranged from 8 1 to 15 1, yields from 76 to 97%, and enantioselectivities from 81 to 94% ee in the case of aliphatic ketenes 66 or 89 to 98% ee for ketenes bearing an aromatic substituent. Applying complexes 65 or the more bulky and less electron-rich 64b, ee values below 5% were obtained. 

Scheme 10.34 Cu-catalysed Mannich-type reactions of A -sulfonyl imines with Fes-ulphos ligand.

This methodology has been repeated to give dendrimers up to the third generation. A variation of this strategy consists of utilizing the phosphine Ph2PCH2OH in a Mannich-type reaction with the terminal NH group on the cyclophosphazene in the second step of the dendrimer... 

Y(03SCF3)3 to afford a monoaminoalkylation product in good yield in aqueous media.40 Zinc tetrafluoroborate is also highly effective for such couplings in aqueous THF.41 Kobayashi also reported a Mannich-type reaction of imines with silyl enolates catalyzed by neutral salts such as sodium triflate in water as a suspension medium. Unusual kinetic behavior indicates that the presence of the Mannich adduct facilitates the rate of its formation.42... 

On the other hand, Kobayashi has developed a Bronsted acid-combined catalyst for aqueous Mannich-type reactions. Three-component Mannich-type reactions of aldehydes, amines, and ketones (e.g., benzaldehyde, p-anisidinc. and cyclohexanone) were efficiently... 

It has also been shown that dimethylsilyl enolates can be activated by diisopropylamine and water and exhibit a high reactivity toward iV-tosyl imines to give Mannich-type reaction products in the absence of a Fewis acid or a Bronsted acid.51 For example, the reaction of [(1-cyclohexen-l-yl)oxy]dimethylsilane with 4-methyl-A -(phenylmethylene)benzene sulfonamide gave re/-4-methyl-N- (f )-[(15)-(2-oxocyclohexyl)phenyl-methyl] benzenesulfonamide (anti-isomer) in 91% yield stereoselectively (99 1 anti syn) (Eq. 11.30). On the other hand, Fi and co-workers reported a ruthenium-catalyzed tandem olefin migration/aldol and Mannich-type reactions by reacting allyl alcohol and imine in protic solvents.52... 

More recently, asymmetric Mannich-type reactions have been studied in aqueous conditions. Barbas and co-worker reported a direct amino acid catalyzed asymmetric aldol and Mannich-type reactions that can tolerate small amounts of water (<4 vol%).53 Kobayashi found that a diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF2, a chiral diamine ligand, and trifluoromethanesul-fonic acid (Eq. 11.31).54 The diastereoselective Mannich-type reaction... 

Another specific monosubstitution which does not occur on phosphorus but on the substituents linked to phosphorus consists of a Mannich type reaction between Ph2PCH2OH and dendrimers bearing NH groups in a position relative to the terminal phosphorus atoms (Scheme 22). This reaction only occurs on one of the two NH chain ends, and no disubstitution takes place here [21]. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

The catalytic asymmetric nitro Mannich-type reaction using the complex Yb, K, and binaphthol gives the best result (see Eq. 4.141).206 The reaction conditions are important to get a good ee, where nitromethane is added very slowly over 27 h. 

Catalytic amounts of I fCl4-AgC104 and Hf(OTf)4 are used for activation of acid halides and acid anhydrides for Friedel -Crafts acylation (Scheme 42) 178 the reactions of both reactive and unreactive aromatic substrates proceed smoothly in the presence of Hf(OTf)4. Furthermore, the Fries rearrangement179,180 and direct C-acylation of phenolic compounds181,182 take place using Hf(OTf)4. Formation of esters and Mannich-type reactions and allylation of imines have been also reported.152... 

Recently, novel bifunctionalized zinc catalysts have been developed (compounds (N) and (P), Scheme 55). They have both Lewis-acid and Lewis-base centers in their complexes, and show remarkable catalytic activity in direct aldol reactions.233-236 A Zn11 chiral diamine complex effectively catalyzes Mannich-type reactions of acylhydrazones in aqueous media to afford the corresponding adducts in high yields and selectivities (Scheme 56).237 This is the first example of catalytic asymmetric Mannich-type reactions in aqueous media, and it is remarkable that this chiral Zn11 complex is stable in aqueous media. 

Another recent example is the asymmetric Mannich-type reaction of hydroxyketones using a ZnEt2-BINOL complex as a catalyst.429 The complex provided superior enantioselectivity and had a very high turnover number. 

Moedritzer, K. and Irani, R.R., The direct synthesis of a-aminomethylphos-phonic acids. Mannich-type reactions with orthophosphorous acid, /. Org. Chem., 31, 1603, 1966. 

Titanium enolates of various carbonyl compounds play an increasingly important role in Mannich-type reactions with different electrophiles. Recently, Liotta and co-workers reported a novel diastereoselective addition of chloro-titanium enolate 80 of iV-acylthiazolidinethione to various types of O-methyl oximes to afford the desired anti-azetines, precursors of a,/3-disubstituted /3-amino carbonyl derivatives 82 (Scheme 32).109... 

Zirconium enolates of various carbonyl compounds have also been investigated for Mannich-type reactions with different electrophiles. According to Shibasaki s method,148 the coupling reaction between a 3-acetoxy-4-alkyl-/3-lactam and the in r(/ -generated zirconium enolate 96 of a cyclohexanone derivative was realized as a key step during the total synthesis of an anitibiotic (Scheme 42).117,149... 

Recently, ruthenium-catalyzed tandem olefin migration/aldol-type or Mannich-type reactions have been developed with aldehydes or imines and allylic alcohols (Scheme 74). 

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