Amines Mannich reaction with

The desired pyridylamine was obtained in 69 % overall yield by monomethylation of 2-(aminomethyl)pyridine following a literature procedure (Scheme 4.14). First amine 4.48 was converted into formamide 4.49, through reaction with the in situ prepared mixed anhydride of acetic acid and formic acid. Reduction of 4.49 with borane dimethyl sulfide complex produced diamine 4.50. This compound could be used successfully in the Mannich reaction with 4.39, affording crude 4.51 in 92 % yield (Scheme 4.15). Analogous to 4.44, 4.51 also coordinates to copper(II) in water, as indicated by a shift of the UV-absorption maximum from 296 nm to 308 nm. 

An indole protected by a Mannich reaction with formaldehyde and dimethyl-amine is stable to lithiation. The protective group is removed with NaBH4 (EtOH, THE, reflux). The related piperidine analogue has been used similarly for the protection of a triazole. ... 

Recent efforts in the development of efficient routes to highly substituted yS-ami-no acids based on asymmetric Mannich reactions with enantiopure sulfmyl imine are worthy of mention. Following the pioneering work of Davis on p-tolu-enesulfmyl imines [116], Ellman and coworkers have recently developed a new and efficient approach to enantiomerically pure N-tert-butanesulfmyl imines and have reported their use as versatile intermediates for the asymmetric synthesis of amines [91]. Addition of titanium enolates to tert-butane sulfmyl aldimines and ketimines 31 proceeds in high yields and diastereoselectivities, thus providing general access to yS -amino acids 32 (Scheme 2.5)... 

A beautiful example of a domino [3+3]-sigmatropic rearrangement is the synthesis of the enantiopure antifungal antibiotic (-)-preussin (4-14) by Overman [5], which starts from the amine 4-10 and decanal to give the iminium ion 4-11 (Scheme 4.3). This undergoes a [3+3]-sigmatropic rearrangement to provide 4-12, followed by a Mannich reaction with the formation of 4-13. 

Phosphorous acid has also been of use for additions to imines. Originally investigated by Moedritzer and Irani,241 who developed a Mannich-type procedure for the preparation of phosphorus-centered species, the approach was found later to be useful for both primary and secondary amines in reaction with formaldehyde and phosphorous acid. The approach was later used for the preparation of a cationic exchange resin using a polymer substrate.242... 

Regioselective aminomethylation and subsequent cyclization of methyl 2,4-dihydroxybenzoate 517 was accomplished through a Mannich reaction with formaldehyde and primary amines in methanol to yield 3-substituted-3,4-dihydro-2/7-l,3-benzoxazine derivatives 518 (Equation 60). Simultaneous mixing of the reactants resulted in poor yields, but good yields were achieved by the pretreatment of paraformaldehye with a primary amine to form a Schiff base, followed by the addition of compound 517 <2001TL7273>. 

As a further illustration of the reactivity of the 3 position toward electrophiles, the methoxyindole (25-1) readily undergoes Mannich reaction with formaldehyde and dimethylamine to afford the aminomethylated derivative (25-2). Treatment of that intermediate with potassium cyanide leads to the displacement of dimethylamine and the formation of the nitrile (25-3), possibly by an elimination-addition sequence involving a 3-exomethylene-indolenine intermediate. The protons on the methylene group adjacent to the nitrile are quite acidic and readily removed. Reaction of (25-3) with methyl carbonate in the presence of sodium methoxide gives the carbo-methoxylated derivative (25-4). Catalytic hydrogenation leads to reduction of the nitrile to a primary amine. There is thus obtained the antihypertensive agent indorenate (25-5) [26]. 

Aliphatic aldehydes and ketones react with aziridines to form relatively stable half aminals, eg, aziridine reacts with formaldehyde to form Ai-hydroxymethylaziridine [20276-43-1]. Half aminals can be converted to full aminals by reaction with a further secondary amine, isomerized to oxazolidines by the action of heat or used in a Mannich reaction for the ring aminomethylation of phenols, although this reaction gives only moderate yields (218-227). 

TNT undergoes the Mannich reaction with formaldehyde and various secondary amines (Refs 16 40) ... 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

A closely related synthesis of symmetrically substituted bispidinones 19a-w is provided by the Mannich reaction with acetone derivatives 319, paraformaldehyde, and the acetate salts of various amines. Such a reaction is formally a C2N + C2N + 2C synthesis but is reported here because of its relationship to the above bispidinone synthesis. In this case the intermediate piperidinone cannot be isolated but once formed, it reacted with the primary amine and formaldehyde to give the eight-membered ring <1995T2055, 19970M1167>. Similarly, the diamine 320 reacted with dibenzyl ketone and formaldehyde to give the macrocycle 321 in 48% yield <1995T4819>. 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

Yi, L. and Xu, X., Mannich reaction with ar-ylaminc a.s amine component. VIII. Mannich reaction of arylaminc with 2,4-pentanedionc or 3-mcthyl-2,4-pentanedionc, Beijing Shiftm Daxue Xuebao, 54, 1990 Chem. Abstr., 114, 122251, 1991. 

In general, amines of type 565 arc more frequently preferred as they expose several sites to Mannich reaction with, for example, phenols. The molar ratio of phenol to amine adopted for this type of synthesis is in fact often less than 2 1. Studies are being conducted into the influence of this molar ratio on the dispersing, antifoulant, etc., properties of the products obtained. ... 

Guang-Xu, C., Xiu-Juan, X., and Lijun, I,., Mannich reaction with arylamincs as amine components, Chem. J. Chinese Univ., 3, 8.3, 1982. 

Solov eva, S. Y., Rainah, S. M., and Ginak. A. I., Study of the reactivity and tautomcrism of azolidines. 42. 2-lminothia/olidin-4-oncs in a Mannich reaction with secondary amines. Khim. Geieroisikl. Soedin., 1.352, 1983 Chem. Abstr.. 100, 103230. 1984. 

Alkylation at the 6-NH2 group similarly may also occur by Mannich reactions with an amine and formaldehyde. Thus morpholine and adenine afforded the diaminomethylated derivative (185) (67AP1000). 

Naskar, D., Roy, A., Seibel, W. L., Portlock, D. E. Novel Petasis boronic acid-Mannich reactions with tertiary aromatic amines. Tetrahedron Lett. 2003, 44, 5819-5821. 

The Morita-Baylis-Hillman reaction and its aza-variant - the reaction of an electron-deficient alkene with an aldehyde (MBH) or an imine (aza-MBH) - provide a convenient route to highly functionalized allylic alcohols and amines. This reaction is catalyzed by simple amines or phosphines, which can react as a Michael donor with an electron-deficient alkene, generating an enolate intermediate. This intermediate in turn undergoes the aldol or Mannich reaction with electrophilic C=0 or C=N bonds, respectively, to deliver allylic alcohols and amines. 

Reactions of 2-methylfuran with aqueous formaldehyde and secondary amines have been reported using a variety of procedures. Thus, 2-methylfuran, formaldehyde and dimethylamine react in aqueous acetic acid at 100 °C to give the expected product (equation 27) in 69-76% yield. Remarkably, it is reported that attempted Mannich reactions with furan itself yields no liquid amine. It has been suggested that this type of reaction can only be carried out with alkyl-substituted furans, because of the marked activating effect of methyl substitution on electrophilic substitution reactions. 

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