Mannich reaction with formaldehyde

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. ... 

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. 

The derivative from an isomeric fused system has been described as a sedative-hypnotic compound. The synthesis starts by condensation of the aminopicoline 32 with the haloketone 33. The resulting pyrrolo[l,2-a]pyridine 34 then undergoes a Mannich reaction with formaldehyde and dimethylamine to give the aminomethylated derivative 35. After quatemization of the di-methylamino group in 35 with methyl iodide, the ammonium group is displaced by cyanide to... 

Inclusion of an acetylenic linkage as part of the side chain is apparently consistent with antidepressant activity. Reaction of propargyl magnesium bromide with dibenzocycloheptadieneone leads to carbinol 82. A Mannich reaction with formaldehyde and dimethylamine leads to 83 which, upon dehydration... 

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]. 

Oxazolidin-2-one (202) has been attached to poly(ethylenimine) (203) by Mannich reaction with formaldehyde (Scheme 97) (72NKK1179). The resultant polymer (204) was a... 

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

The exocyclic amino group of 5-aminotetrazole is reactive in nucleophilic substitution of halogen atoms in halonitrobenzenes. For example, the synthesis of 5-picrylaminotetrazole 406 is based on this process <1999THS(3)467>. Finally, 5-aminotetrazole and l-methyl-5-aminotetrazole 407 undergo a Mannich reaction with formaldehyde and trinitromethane with formation of products 408 (R = H, Me) . 

Reaction of cyclobutadiene-iron tricarbonyl with methylchlorothio-formate followed by hydrolysis gives rise to cyclobutadienecarboxylic acid-iron tricarbonyl (XII). A Curtius rearrangement of the acid azide derived from Complex XII affords aminocyclobutadiene-iron tricarbonyl (XIII). The dimethylaminomethyl derivative (XIV) is readily available through the Mannich reaction with formaldehyde and dimethylamine. The chloromercury cyclobutadiene complex (XV) is produced upon reaction of Complex III with Hg(OAc)2, followed by treatment with hydrochloric acid. In the simplest substitution reaction, treatment of cyclobutadiene-iron tricarbonyl with CF3COOD produces a mixture of deuterated derivatives of Complex III. 

Total syntheses of ( )-capaurine (194 R1 = R2 = R4 = R5 = Me, R3 = OH),209 ( )-isocorybulbine (195 R1 = Me, R2 = R3 = H, R4 = R5 = OMe),202 ( )-kikemanine (194 R1 = R2 = R4 = Me, R3 = R5 = H),210 and ( )-0-methylcaseadine (202)211 have been reported. In all cases, conventional routes involving Bischler-Napieralski cyclization to form benzylisoquinoline derivatives and subsequent insertion of the C(8)-carbon by reaction with formaldehyde were adopted. A further example of para-activation by an ethoxycarbonyl-amino-function for the Bischler-Napieralski reaction may be noted.211 In the synthesis of capaurine, the presence of the bromo-function in compound (203) forced the Mannich reaction with formaldehyde to produce the tetracyclic derivative (204) rather than the normally more favourable mode of cyclization para to the hydroxy-group. Debromination was effected at a later stage with zinc powder in 50 % acetic acid solution.209... 

By the reaction of cyanuric acid with formaldehyde or by Mannich reaction with formaldehyde and diethanolamine interesting polyolic starters with heteroxyxlic triazinic structure are formed [31,41] ... 

Position 6 of pyrido[2,3-r7]pyridazine-5,8(677,7i/)-dione can be alkylated by a Mannich reaction with formaldehyde/morpholine to give 13.91... 

The typical ring positions available for the introduction of carbofunctional groups by exchange of hydrogen are the various -CONH— functions of pyrido[2,3-t/]pyrimidinones.87 265 322 324 For alkylation or acylation reactions of pyrido[2,3-cf]pyrimidine-2,4(l//,3//)-diones 4, in most cases the NH groups are converted into the respective anions by sodium hydride78 322 or sodium ethoxide.323 Mannich reactions with formaldehyde/piperazines have been reported,323 as has been the introduction of propynyl groups under Mitsunobu conditions.324... 

Dichloro-phenoxy acetic acid undergoes Friedal-Craft s reaction with 4-butyryl chloride to yield the corresponding 4-butyryl analogue. This is subsequently subjected to Mannich reaction with formaldehyde and dimethylamino thereby introducing the methylene group caused by thermal decomposition, yields the official compound. 

Spending f-butylcarboxy anhydride (B0C2O). Hydrogenolysis (H2 with Pd/C) permitted the removal of the benzyl protecting group, and the half-acid ester underwent decarboxylation. A Mannich reaction with formaldehyde in the presence of NJ -dimethylamine followed by deprotection (removal of the THP protecting group) resulted in hydroxydiene formation. 

With the exception of formaldehyde, aldehydes (R" H) are prochiral, and the chiral center in the Mannich base appears on the carbonyl C atom of aldehyde. When the prochiral C-H acid component, usually a ketone, enters the Mannich reaction with formaldehyde, a chiral center is formed on the a-C atom of the C-H acid partner (Scheme 4.47). 

Some methods for the synthesis of thiophene-substituted 1,4-diketones begin with the transformation of acetylthiophene. 2-Acetylthiophene 61 is reacted in a Mannich reaction with formaldehyde and dimethylamine to yield the corresponding Maimich base 62 in 70% yield. The Mannich base 62 is then subjected to a Stetter reaction [109] which results in l,4-di-(2 -thienyl)-l,4-butanedione 63 in 70% yield via the cyanhydrine of 2-thiophenecarbaldehyde [110]. Reaction of Mannich base 62 with the isomeric 3-thiophenecarbaldehyde under the same conditions results in l-(2 -thienyl)-4-(3 -thienyl)-l,4-butanedione 64 in lower (35%) yield [Eq. (27)] [110]. 

The reaction can be carried out by heating TNT in a basic solution of aqueous formaldehyde. TNT is only poorly soluble in this solution, however. Better results are obtained when acetone is used as a cosolvent. TNT undergoes the Mannich reaction with formaldehyde and various secondary amines according to the equation ... 

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