Acetals Mannich reaction

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 important extension of these reactions is the Mannich reaction, in which aminomethyl-ation is achieved by the combination of formaldehyde, a secondary amine and acetic acid (Scheme 24). The intermediate immonium ion generated from formaldehyde, dimethyl-amine and acetic acid is not sufficiently reactive to aminomethylate furan, but it will form substitution products with alkylfurans. The Mannich reaction appears to be still more limited in its application to thiophene chemistry, although 2-aminomethylthiophene has been prepared by reaction of thiophene with formaldehyde and ammonium chloride. The use of A,iV-dimethyf (methylene) ammonium chloride (Me2N=CH2 CF) has been recommended for the iV,iV-dimethylaminomethylation of thiophenes (83S73). 

In a modified approach, the carbolinyl acetate 393 underwent a Mannich reaction with formaldehyde and acetone to give the keto ester 396 which, with base, cyclized to the diketone 397. This diketone (397) has recently been used to prepare a number of interesting pentacyclic compounds. 

A rather more complex amino alcohol side chain is accessible by a variation of the Mannich reaction. Taking advantage of the acidic proton in acetylenes, propargyl acetate (62) is condensed with formaldehyde and dimethylamine to give the acetylated amino... 

Finally, a Mannich reaction of with formaldehyde and 4-acet-yl-p-benzodi oxane ( ) leads to pyrroxan (48). 

The condensation of nitro compounds and imines, the so-called aza-Henry or nitro-Mannich reaction, has recently emerged as a powerful tool for the enantioselective synthesis of 1,2-diamines through the intermediate /3-amino nitro compounds. The method is based on the addition of a nitronate ion (a-nitro carbanion), generated from nitroalkanes, to an imine. The addition of a nitronate ion to an imine is thermodynamically disfavored, so that the presence of a protic species or a Lewis acid is required, to activate the imine and/or to quench the adduct. The acidic medium is compatible with the existence of the nitronate anion, as acetic acid and nitromethane have comparable acidities. Moreover, the products are often unstable, either for the reversibility of the addition or for the possible /3-elimination of the nitro group, and the crude products are generally reduced, avoiding purification to give the desired 1,2-diamines. Hence, the nitronate ion is an equivalent of an a-amino carbanion. 

Entry 6 is analogous to a silyl ketene acetal rearrangement. The reactant in this case is an imide. Entry 7 is an example of PdCl2-catalyzed imidate rearrangement. Entry 8 is an example of an azonia-Cope rearrangement, with the monocylic intermediate then undergoing an intramolecular Mannich condensation. (See Section 2.2.1 for a discussion of the Mannich reaction). Entry 9 shows a thioimidate rearrangement. 

The wide latitude of structural variation consistent with bioactivity in this series is illustrated by the observation that antiinflammatory activity is maintained even when the second aromatic group is attached directly to the pyrrole nitrogen rather than to the heterocyclic ring via a carbonyl group as in the previous case. Condensation of p-chloroaniline with hexane-2,5-dione (or its dimethoxy-tetrahydrofuran equivalent) affords pyrrole 7. The acetic acid side chain is then elaborated as above. Thus, Mannich reaction leads to the dimethylaminomethyl derivative 8, which is in turn methylated (9) the quaternary nitrogen replaced by cyanide to afford 10. Hydrolysis of the nitrile then gives clopirac (11). 

Hydroxyprotoberberine 59a and ( )-corytencine (98) led to 13-acetoxy compounds 104,105, and 107 moreover, the 2,3,9,10,12-pentaoxy-genated protoberberine 108 was also obtained from 98 via the p-quinol acetate 106 through a retro-Mannich reaction followed by recyclization (74,75). Oxidation in dichloromethane instead of acetic acid proceeded differently, namely, 97 and 98 led to pentaoxygenated protoberberines 103 and 109 by introduction of an acetoxyl group at C-4 and C-12, respectively, via o-quinol acetates (76). 

Malonic ester syntheses, 30, 7 Malononitrile, 37, 53 Malonyl dichloride, 33, 20 Mandelic acid, 36, 3 Mandelic acid, />-bromo, 35,11 Mannich reaction, with acetone, 37,18 Mercaptoacetaldehyde, diethyl ACETAL, 35, 51... 

In a related publication, Kobayashi and his team reported on Zr-catalyzed asymmetric Mannich reactions that utilize the more electron-rich oxygenated ketene acetals shown in Scheme 6.28 [93], A noteworthy aspect of this study was that the levels of syn/anti diaste-reocontrol proved to be dependent on the nature of the alkoxide substituent whereas the (3-TBS acetals predominantly afforded the syn isomer, the OBn derivatives afforded a larger amount of the anti isomer. As before, the presence of an additive, this time 1,2-dimeth-ylimidazole (DMI), proved to be important with regard to the level of Ti-facial selectivity. The phenol activating group can be removed by the same procedure as reported previously, with essentially identical degrees of efficiency (see Scheme 6.27). 

Scheme 6.28. Zr-catalyzed enantioselective Mannich reactions of functionalized ketene acetals deliver high enantio- and diastereoselectivity.

Related catalytic enantioseiective processes Representative examples of other catalytic asymmetric Mannich additions are depicted in Scheme 6.31. In 1997, Tomioka demonstrated a Li-catalyzed synthesis of functionalized p-lactams that proceeds through a catalytic enantioseiective Mannich reaction (promoted by 103) [95], and a year later Lectka and his team published a series of reports concerning additions of silyl ketene acetals... 

Mannich reaction of 2-cyloalkyl(heteroaryl)-6-aryl-imidazo[2,l-A][l,3,4]thiadiazoles 161 with formaldehyde in the presence of cyclic bases (piperidine and pyrrolidine), in methanol with a catalytic amount of acetic acid, gives the corresponding C-alkylated derivatives 172 (Equation 8) <2006BMC3069>. 

Interestingly, fundamentally different stereoinduction mechanisms have been proposed for the activation of a number of related imine substrates, studies that resulted in the development of simple and highly effective new catalytic systems (27) for the addition of silyl ketene acetals to Al-Boc-protected aldimines (Mannich reaction) (Scheme 11.12c). ... 

The Akiyama group tested various BINOL phosphates 3 as catalysts for the indirect Mannich reaction of aldimines 8 derived from 2-aminophenol with silyl ketene acetals 9 (Scheme 4). All of these Brpnsted acids furnished P-amino ester 10a in (nearly) quantitative yields. Both the reaction rates (4-46 h) and the enantioselectivities (27-87% ee) were strongly dependent on the nature of the substituents at the 3,3 -positions. 

Scheme 5 Mannich reaction of silyl ketene acetals...

Three years after the discovery of the asymmetric BINOL phosphate-catalyzed Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended these transformations to the use of simple ketones as nucleophiles (Scheme 25) [44], Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence of chiral phosphoric acids (R)-3c, (/ )-14b, or (/ )-14c (0.5-5 mol%, R = Ph, 4-Cl-CgH ) to give P-amino carbonyl compounds 69 or 70 in good yields (42 to >99%), flnfi-diastereoselectivities (3 1-49 1), and enantioselectivities (72-98% ee). 

Scheme 6.49 Typical Boc-protected 5-amino acid derivatives obtained from 48-catalyzed Mannich reactions of N-Boc-protected aldimines with silyl ketene acetal.

The mechanism of the Mannich reaction is similar to that of the Vilsmeier reaction as the electrophile is also a methyleniminium cation, formed this time from a condensation of dimethylamine and formaldehyde in acetic acid solution (Scheme 7.7a). This reacts with indole to yield 3-(A, 7V-dimethylaminomethyl)indole (although not shown, it is possible that initial attack occurs at N-1 and rearrangement of the side chain to C-3 takes place in a follow-up step) (Scheme 7.7b). Scheme 7.7... 

Finally, Ramsh and co-workers methylated 133 and isolated a 3 1 mixture of 135 and 136 albeit, in only 35% combined yield. The Russian authors offered a much different mechanistic rationale to account for these results than earlier work. Mannich reactions of 68 lead to markedly different results depending on the amine component (Schemes 6.36 6.37). For example, 137 was isolated in poor yield after refluxing a mixture of 68, benzylamine, paraformaldehyde, and acetic acid in methanol.The same material was also prepared from 138 under similar conditions. In a continuation of this work, Ramsh and co-workers investigated reactions using other primary and secondary amines. When 68 was treated with an excess of formalin and a secondary amine either 139 or 140 was isolated, albeit in fair to modest yield. However, some primary amines gave rise to the oxa-zolo[3,2-fl]l,3,5-triazines 141a-d, whereas other primary amines led to the... 

Mannich reaction Pyrrole and alkyl substituted furan undergo the Man-nich reaction. Thiophene also undergoes this reaction, but, instead of acetic acid, hydrochloric acid is used. 

Indole (I) condenses with formaldehyde and dimethylamine in the presence of acetic acid (Mannich reaction see Section VI,20) largely in the 3-position to give 3-dimethylaminomethylindole or gramine (II). The latter reacts In hot aqueous ethanol with sodium cyanide to give the nitrile (III) upon boiling the reaction mixture, the nitrile undergoes hydrolysis to yield 3-indoleacet-amide (IV), part of which is further hydrolysed to 3-indoleacetic acid (V, as sodium salt). The product is a readily separable mixture of 20 per cent, of (IV) and 80 per cent, of (V). 

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